Methods and devices for conduit occlusion

ABSTRACT

The present invention comprises systems, methods and devices for the delivery of compositions for occluding or of means for opening conduits. The implantable occlusive material may be delivered pre-formed or in situ cured and, may be a resorbable material that supports tissue ingrowth that eventually replaces the material leaving little or no original material in place. The delivery system is positioned to allow for placement of the occlusive material into the body conduit. Use of delivery systems, methods and devices for re-opening an occluded body conduit are also included.

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/371,669, filed Apr. 1, 2019; which is a continuation of U.S. patentapplication Ser. No. 16/144,033, filed Sep. 27, 2018, now U.S. Pat. No.10,292,732; which is a continuation of U.S. patent application Ser. No.15/793,306, filed Oct. 25, 2017, now U.S. Pat. No. 10,111,687; which isa continuation of U.S. patent application Ser. No. 15/082,912, filedMar. 28, 2016, now U.S. Pat. No. 9,839,444; which is a continuation ofU.S. patent application Ser. No. 14/705,390, filed May 6, 2015, now U.S.Pat. No. 9,308,023; which is a continuation of U.S. patent applicationSer. No. 13/684,529, filed Nov. 24, 2012, now U.S. Pat. No. 9,034,053;which is a continuation of U.S. patent application Ser. No. 13/285,744,filed Oct. 31, 2011, now U.S. Pat. No. 8,316,854; which is acontinuation of U.S. patent application Ser. No. 11/065,886, filed Feb.24, 2005, now U.S. Pat. No. 8,048,086; which claims the priority of U.S.Provisional Patent Application No. 60/547,491, filed Feb. 25, 2004, andU.S. Provisional Patent Application No. 60/587,604, filed Jul. 13, 2004,each of which is incorporated by reference herein in its entirety.

TECHNICAL FIELD

The present invention relates to methods and devices for occludingconduits. In particular, the present invention is directed to methodsand devices for delivery of compositions that lead to occlusion ofconduits and for later re-opening of such occluded conduits.

BACKGROUND OF THE INVENTION

In the medical and research fields, there are many clinical situationswhere it is desired or necessary to stop the passage, flow or transferof substances within a body tube or conduit by causing an occlusion orblockage. It is often desirable for the occlusion to be re-opened at alater time. Unfortunately, many occlusion techniques are often harmfulor potentially harmful and are not reversible to accommodate changes inthe needs or desires of patients.

One area that has a need for reversible occlusion of a body tube is thecontrol of fertility. Over the last 50 years, the world has experiencedthe highest rates of population growth and the largest annual populationincreases recorded in history. Women account for over 50% of the world'spopulation and play a critical role in family health, nutrition, andwelfare. One of the most significant areas in need of attention andinnovation in women's healthcare is that of contraception, where thereproductive aged woman is currently faced with sub-optimalalternatives.

Over the past 20 years, couples in every world region have adoptedcontraception with increasing frequency as a means of regulating thetiming and number of children. However, in the less developed countriesthere are still a substantial number of women, who wish to controlfertility but are not presently using contraception. Many governmentsworldwide are intervening with policies to provide access tocontraceptive methods to control over-population. In 2000, it wasestimated that 123 million women did not have access to safe andeffective means of contraception. Therefore, the potential for asuitable contraceptive system has widespread implications for the worldpopulation.

Today there are several contraceptive options available, althoughcurrently available options are associated with specific limitations.Some contraceptive options include surgical intervention, such as tuballigation for female sterilization and vasectomy for male sterilization,both of which are invasive and considered non-reversible. Other optionsavailable to women are hormonal contraceptives, which are not suitableor safe for a number of women. Further options include intrauterinedevices that may have significant side effects.

The ideal contraceptive system is one that would provide an immediatelyeffective, reversible, non-hormonal, non-surgical, easy to deliver,office-based solution that does not require anesthesia, patientcompliance, or special equipment, and does not leave a foreign body inplace long-term. None of the current options meets these requirements.

The most widely utilized method of permanent contraception is tuballigation or female surgical sterilization. There are a number of majordrawbacks associated with tubal ligation. The procedure is permanent andinvasive, requires general anesthesia, has a long recovery time, and canresult in post-tubal ligation syndrome. Post-tubal ligation syndromeoccurs when the surgeon closing the fallopian tube inadvertently damagesor destroys blood vessels to the ovaries causing post-menopausalsymptoms of abnormal bleeding, memory loss, confusion, mood swings, andlack of sex drive. In addition, a recent study has found that of all thehormonal and non-hormonal methods of birth control, tubal sterilizationhas the greatest association with development of functional ovariancysts. Further, women who undergo tubal ligation frequently expressregret or seek reversal. Reversal of tubal ligation, when attempted, isdifficult, costly, and frequently unsuccessful.

On the other end of the spectrum, the most widely utilized method ofnon-surgical contraception is the administration of hormonal drugs, suchas implanted hormones or birth control pills. This method ofcontraception is effective only so long as hormones are administered orbirth control pills taken according to a specific regimen. Althoughwidely used, this method of contraception is not suitable or safe forall women. In addition, there is a high failure rate resulting inunintended pregnancies due to patient non-compliance with the dailyregimen of taking pills.

One reversible contraceptive device currently available is theintrauterine device (IUD). There are an estimated 85 to 100 millionwomen worldwide using this method, substantiating the importance ofreversibility. However, given the possible health risks associated withIUDs and patient reluctance to have a foreign body in place for anextended period of time, fewer than 1 million women in the U.S. use thismethod, and many manufacturers have ceased distribution of thesedevices. The health risks include unplanned expulsion requiring removaldue to excessive pain or bleeding, pelvic-inflammatory disease,permanent infertility, ectopic pregnancy, miscarriage and even death.

While the currently available compositions and methods for contraceptionrepresent a significant advancement in the art, further improvementswould be desirable to provide safe, effective and reversiblenon-surgical devices, compositions, and methods for preventingpregnancy. It would be beneficial if these devices, compositions andmethods provided an immediately effective, non-hormonal, non-surgical,easy to deliver, office-based solution that did not require anesthesiaor patient compliance with a daily regimen. It would be furtherbeneficial if these devices, compositions and methods did not requirespecial equipment to undertake a contraceptive procedure or require aforeign body remaining in place over a long period of time. It would befurther beneficial if these devices, compositions and methods weresuitable to reversal. Some or all of these advantages of an idealcontraceptive system are provided by the devices, systems, compositionsand methods of the present invention.

SUMMARY

The present invention comprises methods, systems, and devices for thedelivery of compositions for the occlusion of conduits. In particular,the present invention comprises methods, systems, and devices for theocclusion of conduits in humans or other animals. The devices of thepresent invention are used to deliver compositions comprising materialsthat occlude the conduit. The conduit may be a naturally occurringconduit such as a tube or vessel in the body or may be a conduit thathas been introduced in the body such as a medical device or throughsurgical means. The occlusive material may be a permanent implant or maybe a material that is degraded or resorbed by the body and allows fortissue ingrowth to maintain the occlusion.

The present invention also comprises delivery systems, methods, anddevices for reversing the occlusion. The occlusion may be reversed byremoval of implant materials or tissue ingrowth that are blocking theconduit, by creating a channel through the occlusion, or by creating anew channel around the occlusion.

One aspect of the present invention comprises delivery systems, methodsand devices for occlusion of fallopian tubes and reversal of theocclusion. One embodiment of this aspect is a method that comprisesintroduction of a delivery device system for delivery of occlusivematerial to both fallopian tubes without the necessity to remove,reinsert, or substantially reposition the delivery device. Such a devicemay be sized for each recipient by pre-visualization of the anatomy ofthe recipient. The implanted occlusive material may be permanent or maybe degraded or resorbed by the body and replaced by ingrowth of tissue.Reversal of such occlusion comprises a device that is capable ofremoving the occlusive material. In another embodiment, reversal ofconduit occlusion comprises a device that is capable of forming achannel through or around the material or ingrown tissue. Reversal ofconduit occlusion may further comprise placement of devices, such asstents, to maintain the re-opened channel; these methods of maintainingthe re-opened conduit are also performed through the use of the deliverydevice.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A shows an embodiment of a delivery device for the transcervicaldelivery of occlusive material.

FIG. 1B shows an embodiment of a double lumen catheter.

FIG. 1C shows an embodiment of a cartridge component containing aflowable material, which includes, but is not limited to occlusivematerial or balloon distension material.

FIG. 2A shows a step in an embodiment of a method of the delivery systemfor deploying and using a delivery device wherein the introducer isinserted through the cervix.

FIG. 2B shows a step in an embodiment of a method of the delivery systemfor deploying and using a delivery device wherein two double lumencatheters are deployed contralaterally within the uterine cornua.

FIG. 2C shows a step in an embodiment of a method of the deliverysystem, wherein each catheter is retracted and the operator begins towithdraw the introducer shaft from the uterus.

FIG. 3A shows an embodiment of a delivery system, wherein the deliverycatheters are shown partially extended.

FIG. 3B shows a portion of the delivery system from FIG. 1A wherein theintroducer tip and partially extended catheters are shown in greaterdetail.

FIG. 3C shows an internal view of the delivery system from FIG. 3A.

FIGS. 4A-C show an embodiment of a delivery device stabilizer and itsplacement within a body. 4A shows an embodiment of a delivery devicestabilizer prior to placement in the body. 4B shows the delivery devicestabilizer in place, prior to expansion of the expandable portion. 4Cshows the expandable portion expanded.

FIG. 4D shows an embodiment of a delivery device stabilizer that isslidable on the introducer shaft and incorporates an expandable portion,that is shown unexpanded.

FIG. 4E shows an embodiment of a pre-formed delivery device stabilizerthat is slidable on the introducer shaft.

FIG. 4F shows an embodiment of a delivery device stabilizer mechanismthat is slidable on the introducer shaft and incorporates a cup-shapedbase that fits over the cervix.

FIG. 4G shows the interaction of the delivery device stabilizer shown inFIG. 4F with outer face of the cervix.

FIG. 5A-D show a cervical clamp and its placement. FIG. 5A shows anembodiment of the delivery device in position in a body, incorporating acervical clamp. FIG. 5B shows an embodiment of the delivery device inposition in a body with the cervical clamp in position. FIG. 5C showsaspects of an embodiment of a cervical clamp. FIG. 5D shows aspects ofan embodiment of a cervical clamp.

FIG. 6A-F show embodiments of methods and devices for opening ofocclusions. FIG. 6A shows an embodiment of delivery of one or moresolutions that degrade and remove the occlusion. FIG. 6B shows anembodiment of use of a guide wire or catheter to open the occlusion.FIG. 6C shows an embodiment of use of an expandable member, such as aballoon, to open the occlusion. FIG. 6D shows an embodiment of use of acutting or debriding member to open the occlusion. FIG. 6E shows anembodiment of an energy device to open the occlusion. FIG. 6F shows anembodiment of the conduits after opening.

DETAILED DESCRIPTION

The present invention comprises delivery systems, methods and devicesfor occluding conduits, and methods, systems, and devices for reversingocclusions in conduits. The present invention comprises delivery systemsand methods for occluding conduits in the body through the placement ofocclusive material using a delivery device. One aspect of the presentinvention comprises occluding conduits permanently. In another aspect,the present invention comprises reversibly occluding conduits. Yetanother aspect of the present invention comprises methods, deliverysystems and compositions to occlude the fallopian tubes of a femalemammal, and methods and systems to re-open such occlusions. A furtheraspect of the invention comprises methods, delivery systems, andcompositions to occlude the vas deferens of a male mammal, and methodsand systems to re-open such occlusions. Methods, systems andcompositions of the present invention may be used in embodiments thatpermit non-surgical, office-based reversible sterilization.

The present invention comprises methods for occluding conduits,particularly conduits found in human or other animal bodies. Suchconduits may exist naturally in the body or be present because ofdisease, damage, placement of medical devices or surgical means.

As used herein, the term “conduit” shall refer to any tube, duct, orpassage, whether natural or synthetic, which carries gas, fluids orsolids in a biological system.

As used herein, “occlude” refers to blocking, partially or fully, thetransport of gas, fluids, or solids through a conduit. The term“occlusion,” as used herein, refers to blockage within a conduit whereinsuch blockage results in partial restriction or complete interruption ofthe transport of gas, fluids, or solids through the conduit. As usedherein, “occlusive material” refers to a composition that is capable ofoccluding a conduit by effecting an occlusion therein. As used herein,occlusive or occluding material means the initial composition that isplaced or inserted into the conduit, as well as the composition, whetherthe physical, biological, or chemical nature of the composition haschanged or not, that is in place in the conduit and provides for theinterruption of flow through the conduit. The meaning of the term can bedetermined from its use in the sentence. Occlusive compositions,occlusion compositions, occlusive materials and occlusion materials areterms used interchangeably herein.

As used herein, occlusive material comprises any natural or syntheticcompositions or any combination of natural and synthetic compositionsthat can be placed at the desired site in the conduit using the deliverysystems of the present invention. Occlusive materials of the presentinvention may comprise materials that are fluid, semi-solid, gels,solids, and combinations thereof. The occlusive materials may furthercomprise a pre-formed material that is of a shape or size that occludesthe conduit or may be a material that will take on a form or shape orsize to occlude the conduit. Occlusive materials may further comprisecompositions that cure in situ at the desired site in the conduit. Theocclusive compositions may further comprise materials that polymerize insitu, wherein the polymerization may be initiated either at the site ofinterest in the conduit or prior to placement at the site. Occlusivecompositions may further comprise combinations of two or more of any ofthe foregoing materials. Disclosed herein are exemplary compositions andmaterials suitable for use as occlusive compositions.

As used herein, “cure” means a change in the physical, chemical, orphysical and chemical properties of the occlusive material followingplacement or insertion at the desired site in a conduit.

As used herein, non-invasive visualization or imaging refers to allforms of imaging that do not require the use of ionizing radiation ordirect visualization such as by hysteroscopy. Examples of non-invasiveimaging include all forms of ultrasound or magnetic resonance imaging,which are incorporated within the scope of this definition.

As used herein, the term “delivery system” comprises all componentsnecessary to deliver an occlusive material or all components necessaryto open an occlusion, and may comprise an introducer, delivery device orcatheter(s), combinations thereof, occlusion means or means for openingan occlusion, and any other components necessary for the fullfunctioning of the delivery system.

In general, the methods of the present invention comprise administrationof delivery systems that deliver compositions that are capable ofoccluding conduits. The delivery systems comprise devices that arecapable of delivering occlusive compositions to the desired site.Disclosed herein are exemplary methods, delivery systems, andcompositions for occlusion of conduits of the reproductive tracts ofmammals. Such methods and compositions can be used in otherphysiological systems and biological sites of humans or other animals,and delivery systems for such biological sites are contemplated by thepresent invention.

The present invention also comprises methods for opening, generally there-opening, of occluded conduits. The methods comprise means for removalof the occlusion, including removal of occluding compositions or forformation of openings or channels through or around one or more occludedregions. Means of removal include, but are not limited to, physicalwithdrawal of the occluding composition, destruction of the occludingcomposition using physical, chemical or biological means, canalizationof the one or more occluded regions, and placement of new conduits, suchas stents or bypass materials to restore functionality to the formerlyoccluded region. Disclosed herein are exemplary methods, deliverysystems and compositions for removal of the occlusion of conduits of thereproductive tracts of mammals to restore fertility functionality. Suchrestorative methods and compositions can be used in other physiologicalsystems and biological sites of humans or other animals, and deliverysystems for such biological sites are contemplated by the presentinvention.

One aspect of the present invention comprises methods of contraceptionfor mammalian females that uses ultrasound visualization of a deliverysystem that delivers a resorbable composition to a target site, forexample, from the cornual aspect of the uterus into each fallopian tube,wherein the composition is capable of creating an occlusion in eachfallopian tube.

A further aspect comprises using the delivery system to implantocclusive material. One aspect comprises methods that use ultrasound forvisualization and positioning of the device and monitoring andconfirming the placement of the composition when an ultrasound visiblecomposition is used. The method comprises introduction of the device,including inserting the shaft of the introducer through the cervix untilthe atraumatic tip contacts the uterine fundus as determined bynon-invasive visualization such as ultrasound or through the sensationof the operator. When the tip is appropriately placed, optionally, theoperator may engage a member that aids in stabilizing the deliverydevice, referred to herein as a delivery device stabilizer. For example,this member may be a depth stop, a member which indicates that the tipis in position and the introducer shaft should be not be introduced anyfurther, and includes, but is not limited to, other delivery devicestabilizers such as those shown in FIGS. 4 and 5, or more than onemember that aids in stabilization. With the introducer in position, eachof two double-lumen balloon catheters is introduced through anintroducer channel until it exits the channel in the shaft of theintroducer, and the tip of the catheter is located within the uterinecornua as determined by ultrasound.

A further aspect of the present invention comprises methods wherein eachcatheter undergoes the following steps. At a proximal end of thecatheter, one end of the catheter which is near the handle and distantfrom the delivery end of the catheter, a cartridge containing balloondistension medium is connected to the balloon fitting, the stopcock isopened, and the distension medium is delivered to effect inflation ofthe balloon positioned at the delivery end of the catheter. The stopcockis then closed and the cartridge is disconnected from the fitting. At aproximal end of the catheter, a cartridge containing the occlusivecomposition is then connected to the delivery catheter fitting, thematerial is delivered through the catheter and out of the delivery endof the catheter that is at or adjacent to the delivery site. Thematerial may be delivered directly to the target site or may move fromthe delivery site to the target site location, and the material cures toform the occlusion. Once the material has at least partially cured intoan occlusion, the balloon is deflated. Each catheter is retracted untilit is housed within the introducer shaft or fully removed from theintroducer. If necessary, the delivery device stabilizer is disengaged.The delivery system is then withdrawn from the patient leaving only theocclusion in place. The occlusive material may be delivered sequentiallyor simultaneously to the two fallopian tubes. The device is designed fordelivery of occlusive compositions to two separate sites with minimal tono repositioning and without removal of the device, including theintroducer, until the procedure is complete. One or both of the deliverycatheters may be retracted into the introducer without repositioning orremoval of the entire device.

Yet another aspect of the present invention comprises a delivery systemfor implantation of the occlusive composition into the fallopian tubescomprising a delivery device comprising an introducer with two channels,optionally one or more delivery device stabilizers, a housing meanswhich may function as a handle if needed, means for attachment of one ormore containers of balloon distension medium and the occlusivecomposition, and two catheters for delivery of the occlusivecomposition. The catheters may comprise an end structure, which is aballoon or other similarly functioning member that may hold the catheterin position, prevents leakage of the material from the target site orperforms both functions. The occlusive composition may be mixed prior todelivery and then delivered from the container through the catheters toone or more target sites.

One aspect of the present invention comprises a delivery systemcomprising an introducer, one or more catheters wherein each may have adistinct function or design, and one or more cartridge componentswherein each cartridge may have a distinct design and contain a distinctmaterial.

Now referring to FIG. 1A, an exemplary embodiment of an introducer isshown comprising the following subcomponents: the introducer tip (1)which is shaped for atraumatic insertion through the cervix; theintroducer shaft (3), generally a structure which may be cylindrical innature, which contains two introducer shaft catheter channels (2), whichrun the interior length of the shaft and have openings for insertion ofa catheter into the shaft and for the catheter to exit the shaft; adelivery device stabilizer (4) which in this example indicates theposition of the tip relative to the point of entry, which may bemeasured based on markings along the shaft and which may further serveto hold the introducer in position; a handle (5) which has an ergonomicdesign for gripping by the operator; and a pair of catheter insertionholes (6) through which the delivery catheters can be inserted into theintroducer and guided to the introducer shaft catheter channels (2). Thedelivery device stabilizer (4) shown in this example is a depth stop.

FIG. 1B shows a delivery catheter for delivery of occlusive material,said catheter comprising the following subcomponents: the delivery end(7) of the catheter through which the occlusive material is delivered tothe target site; a balloon (8) which may hold the catheter in positionand may prevent leakage of the occlusive material away from the target;the shaft of the catheter (9) which, in this figure, features apre-formed curve designed to aid in movement of the delivery end of thecatheter from the introducer shaft into the cornual aspect of theuterus, and includes two lumens, one for inflation of the balloon andone for delivery of the occlusive material; a bifurcation (10) of thecatheter lumens; a fitting (11) that mates with a cartridge thatcontains flowable material to be delivered, such as the occlusivematerial; and a fitting with a stopcock (12) that mates with a cartridgethat contains flowable material to be delivered, such as distensionmedia for inflation and deflation of the balloon. One aspect of thepresent invention comprises a delivery catheter that is a double lumendelivery catheter. It should be understood that the delivery cathetermay comprise a number of features and designs known in the art forcatheters and that would be useful for the function of the deliverysystem. In one embodiment of the present invention, the one or morecatheters are disposed within the hollow introducer shaft. The cathetersof the present invention may be single lumen or dual lumen catheters, orother catheters that would function in the present invention. One aspectof the invention comprises a stopcock is used to prevent leakage of theballoon distension medium after placement. It should be understood thatother devices, such as a valve or diaphragm, including a self-sealingdiaphragm, may also serve the same function and be useful in obtainingand maintaining inflation of the balloon of the present invention.

FIG. 1C shows a cartridge (14) which may contain a flowable material(16) wherein the cartridge component comprises the following aspects:the tip of the cartridge (15) that mates with the delivery catheterfitting (11) or a fitting with stopcock (12) as required; the barrel ofthe cartridge (17); a plunger (18) that fits with the barrel of thecartridge (17) so as to form a seal to prevent back-flow of flowablematerial, said plunger allowing the operator to deliver the flowablematerial; and a flowable material (16), wherein the flowable materialmay comprise occlusive material or distension media.

Now referring to FIGS. 2A-2C, wherein a schematic is shown of anexemplary embodiment of a method for deploying and using the exemplarydelivery system shown in FIG. 1 to effect an occlusion in both fallopiantubes of a mammal. It should be understood that not all steps need beperformed in every deployment. Further, it should be understood thatadditional steps may be added as determined by one skilled in the art asnecessary to increase performance, efficacy, or comfort of the subjectundergoing the method depicted in FIG. 2.

In FIG. 2A, the operator holds the introducer handle (5) and inserts theshaft of the introducer (3) through the cervix (20) until the atraumatictip (1) contacts the uterine fundus (19) as determined by tactile feel,non-invasive visualization such as ultrasound, or a combination of bothtactile feel and non-invasive visualization. When the atraumatic tip (1)is appropriately placed, the introducer shaft catheter channels (2) arelocated such that the openings are directed toward the uterine cornua(24). Following contact of the atraumatic tip (1) with the uterinefundus (19), the delivery device stabilizer (4) is moved into position.In one embodiment, the delivery device stabilizer (4) may comprisecomponents or structures that function to ensure that the operatormaintains a fixed position of the introducer shaft, for example forpreventing uterine perforation, as well as maintaining the position ofthe shaft catheter channels (2) throughout the procedure. In anotherembodiment, the delivery device stabilizer (4) may comprise componentsor structures to provide a depth stop mechanism to the delivery device.In still another embodiment, the delivery device stabilizer comprisescomponents or structures to provide a depth stop mechanism andstabilization to the delivery device.

FIG. 2B depicts the use of the delivery system for the introduction ofan in situ curing flowable occlusive material. With the introducer inposition, the operator moves each of two double-lumen catheters througha catheter insertion hole (6) through the introducer shaft catheterchannels until each catheter exits the introducer shaft catheter channel(2), and the delivery end (7) of the catheter is located within theuterine cornua (24) as determined by the operator's tactile feel,non-invasive imaging such as ultrasound, or a combination of feel andimaging. An exemplary embodiment of a double lumen catheter is describedin FIG. 1B. Once the delivery end (7) of the catheter is positionedwithin the uterine cornua (24), the catheter position may be maintainedby a locking mechanism which may be attached to the handle at or nearthe catheter insertion hole (6), at another location within the handle,or by a mechanism that is separate from the handle and which serves tograb, clamp, hold or otherwise stabilize the catheter such that it doesnot move and such that the delivery end remains in the target location.In another aspect of the invention, inflation of the balloon asdescribed below is sufficient to maintain position of the catheter, andno additional locking mechanism may be required. A cartridge (14)containing balloon distension medium (22), which has been previouslyprepared or mixed if such mixing is necessary, is then fitted to afitting with a stopcock (12), the stopcock is opened, and the distensionmedium (22) delivered to effect inflation of the balloon (8). Distensionmedium may comprise any flowable or liquid material suitable forinflation of the balloon (8), such material being chemically compatiblewith the material of the balloon (8) and may be biologically compatiblein the event distension medium is introduced into the uterine cavity orfallopian tubes. Exemplary distension media include, but are not limitedto, air and sterile isotonic saline solution. Following inflation of theballoon (8), the stopcock is then closed, the cartridge disconnectedfrom the fitting (12), and the procedure repeated to inflate the balloonon the contralateral side. The balloons may be distended simultaneouslyusing two cartridges. A cartridge (14) containing a flowable occlusivematerial (23) is then connected to the delivery catheter fitting (11),and the plunger (18) is pressed into the barrel (17) of the cartridge todeliver the flowable occlusive material (23) into and through thecatheter, and exiting through the delivery end of the catheter (7)toward the target location for example, where it cures in situ. Asdepicted in FIG. 2B, occlusive material has been dispensed in the targetarea and has begun to cure in situ, forming an occlusion (25).

FIG. 2C shows the device at completion of the procedure. Once theflowable occlusive composition has reached the appropriate stage ofcuring, from beginning to cure to substantially curing into an occlusion(25), the operator uses the distension medium cartridge to deflate eachballoon, withdrawing the distension medium into the cartridge. Eachcatheter is retracted until it is housed within the introducer shaft (3)or, as shown in FIG. 2C, fully removed from the introducer. Ifnecessary, the delivery device stabilizer (4) is disengaged. Thedelivery device is then withdrawn from the patient, leaving theocclusion in place.

While the exemplary method shown in FIGS. 2A-2C follows a sequence inwhich both balloons are inflated, occlusive material is deliveredthrough both catheters, both balloons are deflated, and the catheterswithdrawn, a procedure in which all actions are completed initially byone delivery catheter followed sequentially by completion of all actionsfor the second delivery catheter is equally contemplated by the presentinvention and can be at the discretion of the operator. Further, itshould be understanded that the exemplary method may comprise, asdepicted in FIG. 2B, the sequential dispensing of occlusive material(23) from each of two delivery catheters placed in the uterine cornua(24), or alternatively simultaneous dispensing of occlusive material(23) through both delivery catheters.

The delivery system may comprise ease of use features as depicted inFIGS. 3A-3C, which show further exemplary embodiments of a deliverysystem. FIG. 3A shows an external view of a delivery device with thedelivery catheters extended, wherein the delivery device comprises thefollowing components: an atraumatic tip (1) of the introducer shaft; aballoon (8), which is depicted in the drawing as being inflated; thedelivery end (7) of the delivery catheter; the shaft of the introducer(3) comprising two introducer shaft catheter channels (2), which run theinterior length of the shaft and have openings for insertion of acatheter into the shaft and for the catheter to exit the shaft; thatcontain the delivery catheters and guide them into position; a deliverydevice stabilizer (4) to aid in correct placement throughout theprocedure; an ergonomically designed handle (5); a slide grip (26) thatis used by the operator to move the delivery catheters into position,wherein the grip has both up and down movement for extension orretraction and side to side movement for rotation of the catheter tipand wherein the position of the grip can be locked in place to preventfurther motion of the catheter once the desired placement has beenachieved; the shaft of the dual lumen delivery catheter (27); aocclusive material ampule (28) containing a flowable occlusivecomposition (23); and, a delivery plunger (29).

FIG. 3B shows an enlargement of the delivery device, as it would appearwhen it is proximal to the target site for delivery, where the numberedcomponents are as described for FIG. 3A.

FIG. 3C shows internal aspects of the delivery device described in FIG.3A, comprising the introducer shaft (3), wherein the introducer shafthas two dual lumen delivery catheters (27) disposed within it; a distalbifurcation housing (30), wherein each dual lumen catheter is directedby the distal bifurcation housing (30) to one of two slide grips (26),allowing for individual manipulation of each catheter by the operator;each catheter shaft continues from the slide grip (26) generally towardsthe delivery plunger (29) wherein the two catheter shafts are eachattached to the occlusive material bifurcation housing (31) having achannel which directs the flowable occlusive material (23) into each ofthe two delivery catheters; and a component (32) capable of piercing theocclusion material ampule (28) when the plunger (29) is depressed toinitiate entry of the material into the delivery catheters. AlthoughFIGS. 3A-3C do not show a mechanism for inflation and deflation of theballoon, it should be understood that the delivery system may includesuch a mechanism. An embodiment of such a balloon inflation mechanism isdescribed in the present invention, although other embodiments of thismechanism could be used therein. A method of use for this embodiment ofthe delivery system may be like that of the delivery system depicted inFIGS. 1A-1C, or claimed herein. For example, the system comprisesintroducing the delivery device transcervically with the deliverycatheters contained within the introducer, each delivery catheter ismoved into position and the balloon inflated, the material is delivered,and the system withdrawn.

Depicted in FIG. 4 are further exemplary embodiments of the deliverydevice stabilizer (4), serving a similar or additional function to thatshown in FIG. 1, which allows for the fixation of the delivery system tothe cervix or hold the delivery device in position during use of thedelivery system of the present invention. These stabilizers may be usedas a component of the delivery device described herein or may be usefulfor holding in position any transcervical device or instrument having ashaft, including, for example, hysteroscopes and uterine cannulas.

FIGS. 4A-4C show a method of use of one embodiment of a delivery devicestabilizer which is slidable on the introducer shaft.

FIG. 4A depicts an example of a delivery device stabilizer (4) that fitsinto the cervical canal and expands to lock in place. Once theatraumatic tip (1) is in position at the uterine fundus (19), a deliverydevice stabilizer can be employed. As shown, the cervical canal (33) hasa larger inner diameter than the introducer shaft (3), which allowsmovement of the shaft when inserted. The cervix (20) has a large enoughopening to allow passage of the delivery device stabilizer (4) into thecervical canal in a collapsed or deflated state. As shown in FIG. 4B,the delivery device stabilizer (4) is moved transcervically into thecanal while the introducer shaft (3) is held in place, with theatraumatic tip (1) of the introducer shaft positioned at the top of theuterine fundus (19). The collapsed expandable portion of delivery devicestabilizer (4) is positioned within the cervical canal while a widerbase, of sufficient size to prohibit entry into the cervix, ispositioned against the external os. FIG. 4C shows the delivery devicestabilizer (4) in the uterine canal, wherein the expandable portion ofthe delivery device stabilizer (4) is expanded or inflated. Whenexpanded, the expansion portion of delivery device stabilizer (4) holdsthe delivery device stabilizer in place and prevents excessive motion ofthe introducer shaft (3). Although the delivery device stabilizer isshown in FIGS. 4B and 4C residing within the cervical canal, the designof this locking mechanism may also be envisioned to lie up to and eventhrough the internal os with any portion of the length designed forexpansion to enhance fixation.

FIG. 4D shows in detail an exemplary embodiment of the delivery devicestabilizer (4) with an expandable portion, wherein the delivery devicestabilizer mechanism may slide on the introducer shaft. The stop has ahollow core (36), which allows it to be mounted on the shaft of theintroducer where it is designed to slide for proper positioning. Anexpandable portion (34) is mounted on a non-expandable portion (37),which is attached to a base portion (35) that is of sufficient size toprohibit passage into the cervix. The expandable portion (34) may be aballoon that is expanded with a distension medium of one or more gasesor fluids, solid or semi-solid materials, to hold it in place. Theexpandable portion (34) may also be a mechanical device such as spiralor straight wire members that are mechanically actuated to effectexpansion. The expandable portion (34) may be expanded after insertionor may be inserted in a partially or fully expanded state prior toinsertion and further expanded as required after insertion into thecervix. Any means for providing an expandable portion that are known tothose skilled in the art is contemplated by the present invention.

FIG. 4E illustrates an exemplary embodiment of a delivery devicestabilizer with a pre-formed internal portion. The delivery devicestabilizer comprises a hollow core (36) for attachment to and slidablemovement relative to the introducer shaft. The stabilizer comprises aportion that fits into the cervix (38) and a base portion that remainsoutside the cervix (35), wherein the portion that fits inside the cervixis shaped such that it locks or wedges into or through the cervicalcanal and limits motion. The shape may be rounded, wedge-shaped, or haveany other geometry that allows a snug fit within the cervical canal. Theportion that fits inside the cervix (38) may be made from a differentmaterial than the outer portion (35) or may be made from a combinationof materials. While rigid materials may be used, materials that arepliable, compressible, or expand in place such as by swelling, or somecombination thereof may be preferred. The delivery device stabilizermechanism may be designed and material selected such that the deliverydevice stabilizer mechanism collapses or is compressed while beingpushed through the cervix and then re-expands upon placement in thetarget location.

FIG. 4F shows an exemplary embodiment of a delivery device stabilizermechanism with a hollow core (36) to fit over a shaft that has a portion(38) that fits into or through the cervical canal as well as a baseportion (35) that has a cup shape that conforms to the outer geometry ofthe cervix. FIG. 4G illustrates placement of the exemplary deliverydevice stabilizer mechanism of FIG. 4F, showing that the base portionwith a cup shape conforms to the outer curvature of the cervix while theinner portion (38) fits within the cervical canal. The shape of theinner portion (38) may be rounded, wedge-shaped, or have any othergeometry that allows a snug fit. The portion that fits inside the cervix(38) may be made from a different material than the outer portion (35)or may be made from a combination of materials. While rigid materialsmay be used, materials that are pliable, compressible, or expand inplace such as by swelling, or combinations of such characteristics maybe used. Either the internal portion (38) or the base portion (35) maybe used alone or in combination as necessary to ensure appropriatefixation, stability, or both. It may be considered that the exemplaryembodiments described in FIG. 4 incorporate the function of a depthstop, as shown in FIG. 1, into the design of the delivery devicestabilizer (4).

FIGS. 5A and 5B show the placement of an exemplary embodiment of adelivery device stabilizer referred to as a cervical clamp. In oneaspect of the present invention, the cervical clamp may be used in thedelivery system that does not incorporate an additional delivery devicestabilizer. In a further aspect of the present invention, the cervicalclamp may be used in a delivery system that also uses one or moreadditional delivery device stabilizers, which may include a depth stop.FIGS. 5A and 5B show a cervical clamp (39) mounted on an introducershaft (3), which is attached to a handle (5). The introducer shaft (3)is positioned such that the tip of the shaft (1) is positioned at theuterine fundus (19). As shown in FIGS. 5A and 5B, the cervical clamp isused in combination with a delivery device stabilizer (4) incorporatinga depth stop function that marks and maintains the insertion position ofthe atraumatic tip (1). The cervical clamp (39) is introduced into thevagina (40) in a closed or folded state, as depicted in FIG. 5A. Theclamp (39) is advanced over the introducer shaft (3) until the leadingedge nears the cervix (20), at which point, it is deployed and attachedto the cervix (20), as depicted in FIG. 5B. The cervical clamp (39)attached to the cervix (20) functions to stabilize the introducer shaft.

FIG. 5C depicts an exemplary embodiment of a cervical clamp in which thegrasping arms (42) may remain in a folded state until acted upon by aforce. The cervical clamp, with a hollow core (36) to allow the clamp tomove over a shaft, includes grasping arms (42), which are actuated toattach to the cervix. In this embodiment, three grasping arms aredepicted. Other embodiments include devices with two, four, five, ormore grasping arms. The grasping arms are positioned such that the tipsof the arms (41) are in close proximity to the introducer shaft on whichthe cervical clamp is mounted. As depicted in FIG. 5C, tabs (43) areprovided that, when squeezed by the operator of the device, cause thearms (42) and tips (41) to move outward, causing the cervical clamp toopen. The clamp (39) is positioned over the cervix (20), and the tabs(43) are released, causing the clamp to fasten or attach to the cervix.The clamp is released by pressing on the tabs (43) to move the arms (42)outward, disengaging the tips (41) from the cervix. A further embodimentof the device may include a mechanism for movement of the clamp (39)relative to the shaft (3) and a mechanism for controlling the movementarms (42), wherein such mechanisms may be incorporated into the handle(S) of the delivery device.

FIG. 5D depicts a further embodiment of a cervical clamp in which thegrasping arms (42) may remain in an open state until acted upon by aforce. In this embodiment, four grasping arms are depicted. Otherembodiments include devices with two, three, five, or more graspingarms. A compression member (44), with a hollow core (36), slidesrelative to the shaft of the clamp (45) and imparts a compressive forceon the arms (42), deforming or moving them into a closed or foldedposition. To attach this embodiment to the cervix (20), the compressionmember (44) is advanced to compress the arms (42) to a folded state asdepicted in FIG. 5A. When the clamp (39) is in place near the cervix(20), the compression member (44) is retracted to allow the arms toopen. Subsequent advancement of the compression member (44) closes thearms (42) of the clamp (39), by deforming or moving the arms (42) tobring the tips (41) in to contact with the cervix (19). The compressionmember (44) may be advanced or retracted by mechanical means such asthreads, ratchet, slider, or other mechanisms. A further embodiment ofthe device may include a mechanism for movement of the clamp (39)relative to the shaft (3) and a mechanism for controlling the movementof the compression member (44) incorporated into the handle (5) of thedelivery system.

The tips of the arms (41) of the cervical clamp (39) may furthercomprise one or more grasping teeth, or may include other shapes ormechanisms for firmer or more comfortable attachment to the cervix (20).The tips (41) and arms (43) may be made from the same material or ofdistinct materials as required; for example, the tips may incorporate amaterial that is compressible and conformable to the cervix and may bedesigned to alter shape when in contact with the cervix to provideincreased comfort or improved gripping. One aspect of the inventionenvisions that the tips (41) interact with the cervix (20) in such amanner that the grip strength of the clamp is sufficiently low that thepatient feels little or no pain with minimal or no anesthesia whilehaving sufficient grip strength to hold, fix, and/or stabilize theposition of the introducer. The cervical clamp (39) has a cylindricalchannel (36), which allows for mounting onto or sliding over theintroducer shaft (3).

FIGS. 6A-6E illustrate exemplary embodiments of conduit occlusionopening or re-opening devices, or reversal devices and methods,particularly for opening or re-opening one or more occluded fallopiantubes. The example discussed herein is directed to opening occludedfallopian tubes, but this description is in no way to be seen aslimiting the methods of the present invention. An introducer shaft (3)with two or more channels may be used to deliver two or more catheters(9) to the area of the fallopian tube occlusion (25). Materials ordevices for opening of occlusions or reversal of occlusions may bedelivered through or mounted on the delivery catheters (9). Occludedfallopian tubes may be treated simultaneously or sequentially. Thedelivery device allows for the opening or re-opening of two or moreconduits without the need for removal and re-introduction or substantialrepositioning of the device. One or more reversal methods may be used incombination to effect re-opening of the occluded conduit. It should beunderstood that, while depicted for use in re-opening occlusion infallopian tubes, the methods and devices described herein may be usefulfor re-opening occlusions in any occluded body conduit. As used herein,the terms opening and re-opening both refer to making a non-functionalconduit functional again by providing an opening through or removing anocclusion.

FIG. 6A depicts the introduction of an enzymatic, solvent, or otherocclusion-degrading solution (46) to the site of the occlusion (25),such that the solution (46) degrades and removes the occlusion (25). Anintroducer shaft (3) is placed in position and delivery catheters (9)are advanced through the shaft through introducer shaft catheterchannels (2), which run the interior length of the shaft and haveopenings for insertion of a catheter into the shaft and for the catheterto exit the shaft such that the catheters reach the occlusion (25). Endstructures (8), which may include a balloon, may be engaged, such asinflated, to limit delivery of the degrading solution to the area ofocclusion (25), and may prevent retrograde flow into the uterus.

FIG. 6B shows a method of reversing an occlusion by passing a guide wireor small catheter (47) through the occlusion (25), thereby clearing theblocked fallopian tube. An introducer shaft (3) is placed in position,and one or more delivery catheters (9) are placed through the shaftthrough introducer shaft catheter channels (2), which run the interiorlength of the shaft and have openings for insertion of a catheter intothe shaft and for the catheter to exit the shaft such that the cathetersreach the occlusion (25) in one or both of the fallopian tubes. A guidewire (47) or a small catheter (47) is passed through the deliverycatheter (9) and advanced across the occlusion (25). The occlusion isremoved or cannulated, thereby reopening the fallopian tube. Materialfor use in the small catheter may be sufficiently stiff to allow formovement across and through the occlusive material or tissue.

As depicted in FIG. 6C, one or more catheters (9) with attached balloon(48) may be placed through an introducer shaft (3) through introducershaft catheter channels (2), which run the interior length of the shaftand have openings for insertion of a catheter into the shaft and for thecatheter to exit the shaft such that the catheters can be advanced suchthat the balloon (48) is within the area of occlusion (25). Inflation ofthe balloon may effect clearing of the occlusion. The catheter withattached balloon may pass directly through the introducer shaft (3) toreach the occlusion (25) or may pass through a larger catheter (notdepicted) that passes through the introducer shaft (3) to the area ofthe occlusion (25). The balloon may be further used to effect deliveryof a stent or other structure that maintains the re-opened channel afterreversal of the occlusion.

FIG. 6D depicts a method of clearing fallopian tube occlusions by usinga cutting or debriding mechanism. The cutting mechanism (49) maycomprise or be similar to, for example, a device for atherectomy(directional coronary atherectomy), rotoblation (percutaneoustransluminal rotational atherectomy), or a cutting balloon. One or moredelivery catheters (9) are passed through an introducer shaft (3)through introducer shaft catheter channels (2), which run the interiorlength of the shaft and have openings for insertion of a catheter intothe shaft and for the catheter to exit the shaft such that the catheterscan be advanced to the vicinity of the occluded region (25). A cuttingdevice (49) is advanced through the delivery catheter (9) to theoccluded region (25). The cutting device is used to remove the occlusion(25), thereby reopening the fallopian tube.

FIG. 6E depicts a method of clearing an occlusion by using anenergy-producing device (50). Ultrasound, RF energy, microwave, laser,radiation, heat, or other energy sources may be used. An introducershaft (3) is placed, and one or more delivery catheters (9) are insertedthrough the introducer shaft through introducer shaft catheter channels(2), which run the interior length of the shaft and have openings forinsertion of a catheter into the shaft and for the catheter to exit theshaft so that the catheters can be provided to the area of the occlusion(25). An energy-producing device (50) mounted on a catheter or wire ispassed through the introducing catheter (9) and into the occluded region(25). The occluded region is subjected to energy from the energy source,which removes the occlusive material and clears the occlusion.

FIG. 6F depicts a uterus that has been subjected to one or more of themethods depicted in FIGS. 6A, 6B, 6C, 6D, and 6E. After treatment, theocclusion has been re-opened or removed, leaving patent fallopian tubes(51). The delivery systems of the present invention comprise means forintroducing delivery devices into the body, means for providingocclusive material such as reservoirs and pumps, devices for in situdelivery of compositions comprising occlusive materials, means forpolymerizing or coagulating the occlusive materials, includingmechanical, biological or chemical means; means for visualization ofprocedures, pre- and post-procedural compositions and methods oftreatment, means and compositions for supporting or inducing tissueingrowth or degradation of the occlusive material, and means forre-opening of the occluded conduit.

The present invention further comprises methods for occluding fallopiantubes that are useful for providing female sterilization. It is wellknown in the art that a primary cause of naturally occurring infertilityin females is blockage of the oviducts from the ovary to the uterus.Females having this natural condition normally do not even realize itexists and do not suffer any adverse side effects besides beinginfertile. Moreover, the condition can often be successfully reversed,thus restoring the ability to bear children. Based upon the observationsof naturally occurring oviductal occlusion, the creation of tubalocclusions by external intervention has arisen as a potential means ofeffecting female sterilization.

Aspects of the present invention comprise a delivery system,compositions comprising one or more occlusive materials, and a methodfor tubal occlusion and more particularly occlusion of the fallopiantubes of a female mammal for the purpose of reversible sterilization. Inone aspect of the invention, the delivery device is inserted eitherdirectly or through an introducer sheath and positioned to reach thearea in which the occlusion is desired while the operator non-invasivelyvisualizes the delivery to ensure correct placement. Once in place, theoperator instills the occlusive agent through a channel in the deliverycatheter, creating the occlusion. The delivery device is then withdrawn,leaving the occlusion in place. Over time, fibrous tissue grows into thematerial as it resorbs, leaving an occlusion fashioned of the patient'sown tissue. The delivery system may be used to deliver an agent, such asa device or composition, to reverse the occlusion, and methods forre-opening the occlusion are described.

As envisioned for female sterilization, a delivery system comprises atranscervical introducer sheath generally made of a standardmedical-grade metal or plastic such as stainless steel, nylon, PTFE, orpolyurethane, which may be naturally sonolucent or may requireenhancement of ultrasound visibility by coating with a sonolucentmaterial or otherwise modifying the material. The sheath may comprise anatraumatic tip to allow for comfortable placement and, combined withselection of a suitably flexible material, to prevent damage to theuterine wall. The introducer shaft has sufficient diameter to allow forintroduction of other components of the delivery system. The introducermay contain one, two or more channels that guide catheters intoposition, for example delivery catheters for delivery of occlusivematerials. The introducer may include a mechanism to modify the angle ofthe introducer relative to the surrounding tissues, such as the cervixor uterus, to allow for a better fit to the anatomy of the individualpatient, including such individual variations as ante- orretroverted/ante- or retroflexed uterus. Modified versions of theintroducer may allow for uses other than for the occlusion of thefallopian tube(s), such as the localized delivery of contrast media forconfirmation of tubal patency or the delivery to or removal from thefallopian tube(s) of other material or devices for diagnosis, treatment,or examination of the tube, including the delivery of systems forre-opening an occlusion. One aspect of the introducer sheath is that itcan be visualized using noninvasive techniques such as ultrasound.Visualization may be used to guide accurate placement and to ensure thatthe tip of the device does not penetrate the uterine wall. A deliverydevice stabilizer may be included to ensure that accurate placement ismaintained throughout the procedure. The delivery device stabilizer maycomprise or include a means to fix or hold the introducer in place, suchas a mechanism or device to attach or hold the introducer within thecervix or to otherwise maintain the device in the desired position,minimizing risk to the patient and allowing the operator greaterflexibility to carry out other aspects of the procedure. Fixation may beaccomplished through physical means such as clamping, suction, wedging,inflation, or by other means that maintain the device in the desiredposition.

A delivery system of the present invention comprises a device that canbe configured in a collapsed, retracted, or folded form for insertionthrough the cervix, which may comprise an introducer sheath. Afterintroduction, the device is positioned allowing an atraumatic tipcontaining a single or multiple holes at the tip of the device to reachthe desired location, such as within the cornual aspect of the uterus ator near the ostium of a fallopian tube. The present invention comprisesa device that has at least one end of a delivery catheter with anopening that is placed within the cornual aspect of the uterus at ornear the ostium of a fallopian tube.

In one embodiment, the delivery device comprises two delivery catheters,with each catheter having its delivery opening positioned simultaneouslyor sequentially at the ostia of both fallopian tubes. In anotherembodiment, such a device may be shaped like a Y, a T, or an arrowwherein the two delivery ends of the shape are positioned within theuterine cornua at or near the ostia. The delivery system may utilizeexisting catheter-based technology, for example, balloon catheters, andmay incorporate standard materials such as Pebax, nylon, PTFE,polyurethane, vinyl, polyethylene, ionomer, polyamide, polyethyleneterephthalate, and other materials. These materials may be naturallysonolucent or may be modified to enhance their ultrasound visibility,such as by coating or the inclusion of air bubbles within the material.Embodiments of the present invention may include a means for controlledflexion or rotation of the delivery system, which may aid in positioningone or more ends at the desired anatomic location. The catheters may bedesigned with one or more curves that ensure that the tip is guided tothe uterine cornua. Such curves may be either pre-formed to suit amajority of female reproductive anatomies or may be selected based onthe individual anatomy of a single female patient.

The present invention comprises methods for occlusion of fallopian tubescomprising delivery of devices, such that the methods incorporateintra-procedure non-invasive visualization without hysteroscopy, andpositioning of the delivery ends of a delivery device within the uterinecornua at or near the ostia of both fallopian tubes without the need forremoval and reintroduction of instrumentation. Embodiments of thepresent invention comprise delivery devices that are sized appropriatelyfor a general population of patients and also comprise delivery devicesthat are custom-fitted and individually tailored to meet individualpatient anatomical needs. Delivery devices taught in the prior art, suchas U.S. Pat. Nos. 5,746,769, 6,145,505, 6,176,240, 6,476,070, 6,538,026,6,634,361, 6,679,266, and 6,684,384, 5,954,715, 6,068,626, 6,309,384,6,346,102, and 6,526,979 do not consider individual patient anatomy, mayrequire the use of a hysteroscope for direct visualization, andnecessitate cannulation of each tube sequentially, with the need toreposition, withdraw and reinsert the device, enhancing the technicaldifficulty of the procedure and consequently the inherent risk offailure.

One aspect of this invention contemplates the use of pre-procedureimaging, such as by ultrasound, to allow for selection or adjustment oflengths and angles of the deployed delivery device and selection ofappropriate delivery device stabilizer to accommodate individual patientanatomy. This pre-procedure imaging is used to rule out anomalies thatmay preclude use of the system and may be used to determine the uterinewidth between the fallopian tubes to select the correct size deliverysystem or to adjust the angle or shape of each of the two delivery endssuch that each would be properly located within the uterine cornua at ornear the ostium of a tube on deployment. Imaging may also elucidate thesize and shape of the cervical os and canal, guiding selection of sizeand shape of delivery device stabilizer or spacer. Alternatively, one ofa set of predetermined sizes of the delivery system could be selectedbased on the pre-procedure imaging information. The ability to adjustplacement of the delivery ends or tips, including the angle and lengthfor each individual end or in combination, during the procedure based ontactile feedback, imaging, or both tactile and imaging information isalso contemplated. Other pre-procedure methods include the use ofhormonal medications to control estrogen/progesterone cycle changes orprevent placement of the device during pregnancy and the use ofpre-operative medications such as anti-infective or immune responsetherapies.

The present invention further comprises post-procedure methods andcompositions. Post-procedure methods may comprise, for example,ultrasound or X-ray visualization, to allow for confirmation that theocclusive material continues to provide an occlusion over time.Post-procedure methods and compositions may further comprise the use ofhormonal agents to prohibit menstrual shedding of the endometrium isalso contemplated to minimize the risk of expulsion for a period oftime, for example to allow for a period of time for resorption of theocclusive material and tissue ingrowth. For example, use of along-acting hormonal medication such as an injectablemedroxyprogesterone acetate depot may serve the function of both thepre- and post-operative hormonal therapy without the need for relianceon patient compliance. Post-operative methods and compositions mayfurther comprise antibiotic or steroidal compositions.

Methods of the present invention comprise visualization of one or moresteps of the methods. Visualization of the insertion, placement of thedevice, and release of the occlusive composition are included in methodsfor providing the occlusive material. Visualization of the occludedregion, removal of the occlusive material, reopening of the conduit andtesting for return of functionality of the conduit are included inmethods for reversing the occlusion of the conduit. Such visualizationmethods are known to those skilled in the art. U.S. Pat. Nos. 4,731,052and 4,824,434 teach that ultrasound may be used for visualization ofinternal structures. The compositions and devices of the presentinvention comprise materials that allow for visualization, such as byultrasound, during the procedure to ensure appropriate patient selectionand device placement and localization, and for post-applicationmonitoring to confirm appropriate material placement and the presence ofan occlusion.

Once the delivery device is appropriately placed, the occlusive materialis introduced through the delivery device to create the occlusion of thefallopian tubes. In one aspect of the invention, the delivery device hasindividual channels in the shaft of the introducer, with capability toprovide a delivery end or tip directed toward the opening of a fallopiantube. An aspect of the invention allows for the simultaneous orsequential delivery of occlusive material to the fallopian tubes withoutthe need to withdraw and reinsert or substantially reposition thedevice. The occlusive material is delivered by actions of the operatormanually or automatically once the device is in position. One aspect ofthe invention contemplates the occlusive material is visualizable bynon-invasive imaging such as ultrasound. Materials may be naturallysonolucent or may be modified to have enhanced sonolucency by theintroduction of materials or bubbles such as microbubbles of air or gas.These microbubbles may be present within the material prior toattachment to the delivery system or may be introduced into the materialduring the delivery process, such as through the use of a cavitationmechanism.

It is contemplated that the methods taught herein are effective with oneapplication of occlusive material to at least one conduit, though themethods comprise at least one application to at least one conduit.Embodiments also comprise one or more applications of occlusive materialto at least one conduit during one delivery cycle. For example, once thedelivery device is in place in the uterus, with at least one end of thedevice at the site or sites to be occluded, occlusive material may beapplied once, and then, without removal, one or more other applicationsof occlusive material are performed. Alternatively, occlusive materialsmay be placed at the site or sites for occlusion over multipletreatments. For each treatment, the delivery device would be insertedand removed. Such multiple applications may occur on consecutive days ofinsertion and removal or the days of insertion and removal may beinterspersed with days of no applications of occlusive material. Suchtreatment regimens may be designed with individual patient needs takeninto account by those skilled in the art, such as the treatingphysicians. Such treatment regimens may utilize the same or differentocclusive compositions at each application.

The occlusive compositions include natural or synthetic materials.Natural materials include those found in animals or plants and notnecessarily in the species in which they are used. Synthetic materialsinclude any materials that can be made by humans or machines inlaboratory or industrial settings. The compositions may comprisematerials that are initially mostly fluid that polymerize in situ tobecome solid materials, may comprise solid materials that may or may notchange properties such as flexibility, once placed at the site or sitesfor occlusion, may comprise a mixture of fluids with gas, solid articlesor both, dispersed therein. The occlusive material compositions may be apre-formed shaped material that is released by the device once one ormore delivery ends are in position, and the compositions may compriseocclusive material that starts as a liquid or semi-solid that cures insitu. The compositions of the present invention may include solidstructures such a stents, rods, pellets, beads, and other tissue bulkingagents that provide a solid structure to the occlusion formed at thesite or sites. Compositions of the present invention may also combinepre-formed structures, such as spheres or particles, with material thatstarts as a liquid or semi-solid and cures in situ, entrapping thepreformed structures.

One aspect of the present invention comprises an occluding compositioncomprising a liquid that is mixed prior to delivery or does not requirepre-mixing such as the single liquid composition, is ultrasound visible,and cures upon delivery into and through the tubal ostia within 5 cm ofthe ostium to provide mechanical blockage and is at least 75% resorbedat a range of between about 30 to about 365 days. In one embodiment, theoccluding composition is not hydrophilic and does not swell in thepresence of fluids in the environment. In another aspect, the occlusivecomposition forming the occlusion may aid in the initiation orstimulation of tissue growth into the occluded site, wherein theocclusion is replaced by tissue that maintains the occlusion afterresorption of the occlusion material. In another aspect, an embodimentof the invention contemplates use of an occlusive material that has afunctional lifespan wherein for a period of time it forms the physicalocclusion or blockage of the lumen, and after period of time, theocclusive material is gone, having been resorbed or degraded, but is notreplaced by tissue ingrowth, so that the lumen is again open andfunctional.

In a further aspect of the present invention, the occlusive materialcomprises a two component liquid comprising a resorbable polymersolution component and a liquid cyanoacrylate tissue adhesive component.The resorbable polymer is a polyester polymer selected from polylactide,polyglycolide or polycaprolactone, or a polyester copolymer selectedfrom poly(lactide/glycolide) acid (PLGA) orpoly(lactid-co-.epsilon.-caprolact-one) (PLCL). The cyanoacrylate tissueadhesive component comprises any of a number of biocompatible alkyl- oralkoxyalkyl-2-cyanoacrylates such as n-butyl-2-cyanoacrylate or2-methoxybutyl-2-cyanoacrylate. The two component liquids are mixedprior to entry in the catheters for delivery. In curing, thecyanoacrylate homopolymerizes and entraps the polyester polymers orcopolymers. The cyanoacrylate adheres to the lumen wall to anchor theocclusion in place.

A single liquid composition is also contemplated. The single liquidcomposition comprises a liquid tissue adhesive, such as a cyanoacrylatewith a nano- or micro-particulate material, which may be made fromresorbable polyesters. In one aspect of the invention, the particles arecapable of visualization by ultrasound. The particles and tissueadhesive are combined prior to delivery to the target site. Thecomposition cures by the homopolymerization of the tissue adhesive,entrapping the particles, and anchors the occlusion in the lumen byadhesion to the lumen wall.

The resorbable nature of the occluding composition and the proximity ofthe occlusion to the ostia, extending over a limited length of thefallopian tube, may allow for ease in the reversibility of thecontraceptive method. As the occlusive implanted composition isresorbed, there is ingrowth of tissue that maintains the occlusion. Thetissue occlusion so formed can be recanalized to provide an open conduitfor fertilization without the need for surgical removal and reappositionof the tube across the area of the occlusion.

A wide variety of materials are known in the art that can be used toform the conduit occlusions of the present invention, such as oviductocclusions. U.S. Pat. No. Re. 29,345 teaches the use of silastic that ispartially pre-formed and partially in situ cured. U.S. Pat. No.4,185,618 teaches the use of a gel-forming carrier substance that holdsin place a tissue fibrosis-promoting material. U.S. Pat. Nos. 4,365,621and 4,509,504 describe the use of a swelling material that is inert andpermanent. U.S. Pat. No. 6,096,052 describes the use of a mesh-basedmaterial that supports fibrous tissue ingrowth. U.S. Pat. No. 4,700,701describes the use of a resorbable plug in combination with physicaland/or chemical means of inducing a scarring reaction. U.S. Pat. No.5,989,580 incorporates the use of a biocompatible, non-degradableimplanted polymer of several types that can be removed by dissolution.U.S. Pat. No. 6,605,294 teaches the use of absorbable polymers,pre-shaped with at least one rod-shaped portion, to occlude fallopiantubes. U.S. Pat. No. 5,894,022 teaches using a composition that may forma degradable mesh. U.S. Pat. Nos. 6,371,975, 6,458,147, and 6,743,248teach the use of a polyethylene glycol and protein composition for theocclusion of vascular access puncture sites. The present inventioncomprises these and other occlusive compositions for blocking a conduitthat may be introduced using the delivery devices of the currentinvention.

One aspect of the occlusive compositions of the current inventioncomprises a resorbable material capable of providing an initialmechanical blockage and initiating or supporting the tissue ingrowthnecessary to create the occlusion and/or an adhesive composition thatmaintains the position of the material during curing and the initialphase of tissue ingrowth. U.S. Pat. Nos. 4,359,454, 6,476,070, and6,538,026 teach the use of cyanoacrylate, and in particular acomposition containing either n-methyl or n-hexyl cyanoacrylate, as aresorbable, yet scar-promoting, material. Other patents teachcompositions of polymerizable monomers, such as cyanoacrylates, alone orin combination with other materials, such compositions that may beuseful as occlusive agents or adhesives in the present invention and/oras resorbable materials capable of initiating or supporting tissueingrowth to form a permanent adhesion. These include U.S. Pat. Nos.5,328,687, 5,350,798, 6,010,714, 6,143,352, 6,174,919, 6,299,631,6,306,243, 6,433,096, 6,455,064, 6,476,070, 6,538,026, 6,579,469,6,605,667, 6,607,631, 6,620,846, and 6,723,144.

A further aspect of the current invention includes materials that aredelivered in a solid or non-solid form which may be used to deliver oradhere materials that may be useful in promoting or forming occlusionsor which may be useful in forming occlusions in and of themselveswhereas such material may be resorbable or permanent. Such materialsinclude dry compositions that hydrate and form crosslinked hydrogels, astaught by U.S. Pat. No. 6,703,047. U.S. Pat. Nos. 5,612,052, 5,714,159,and 6,413,539 teach self-solvating polyester copolymers that formhydrogels upon contact with body fluids. U.S. Pat. No. 4,804,691 teachescompositions of hydroxyl-terminated polyesters crosslinked withdiisocyanate. U.S. Pat. No. 6,723,781 teaches crosslinked, dehydratedhydrogels. Hyaluronic acid based hydrogels are taught in U.S. Pat. Nos.5,866,554 and 6,037,331. Two part hydrogels are taught in U.S. Pat. No.6,514,534. Crosslinked bioadhesive polymers are taught in U.S. Pat. Nos.6,297,337 and 6,514,535. Thermosensitive biodegradable polymers aretaught in U.S. Pat. No. 5,702,717.

The present invention comprises compositions that form an occlusion in aconduit, wherein the occluding material is resorbed or biodegraded bythe body in a range from at least about 20% to about 100%, or in a rangefrom at least about 20% to about 80%, from a range of at least about 20%and about 60%, from a range of at least about 30% to about 50%, from arange of at least about 30% to about 80%, from a range of about 70% toabout 100%, and from a range of about 40% to about 100%. Such resorptionmay occur substantially over a period of time from about 30 days to 365days, from about 30 days to 180 days, from about 30 days to 90 days,from about 60 days to 365 days, from 60 days to 180 days, or from about90 days to 365 days. A composition comprises a material that is resorbedor biodegraded by the body in a range of at least about 20% tosubstantially 100% in a period of time of about 30 days to 365 days,where the initial mechanical occlusion formed by the material ismaintained thereafter by the tissue that grows into the site.

The present invention contemplates use of an in situ curable material,which lowers the risk of expulsion by allowing the material to conformand adhere to the walls of the conduit, or specifically the uterusand/or fallopian tube. Compositions capable of in situ curing preferablycomprise a material that is flowable at a temperature outsidephysiologic limits but curable at physiologic temperatures such as thosetaught by U.S. Pat. Nos. 5,469,867 and 5,826,584. High viscosity liquidscapable of delivering and maintaining materials in place that are usefulfor the present invention are taught in U.S. Pat. Nos. 5,747,058,5,968,542, and 6,413,536. Alternatively, the material may cure oncontact with the tissue environment as described in U.S. Pat. Nos.4,359,454, 6,476,070, and 6,538,026; on contact with a curing agent asdescribed by U.S. Pat. Nos. 5,278,202 and 5,340,849; or on dissipationof the solvent as described by U.S. Pat. Nos. 4,938,763, 5,278,201,5,324,519, 5,487,897, 5,599,552, 5,599,552, 5,632,727, 5,702,716,5,728,201, 5,733,950, 5,736,152, 5,739,176, 5,744,153, 5,759,563,5,780,044, 5,792,469, 5,888,533, 5,990,194, 6,120,789, 6,130,200,6,395,293, 6,461,631, 6,528,080, and Re. 37,950 as well as world-widepatent numbers WO 97/42987, WO 99/47073, and WO 00/24374.

The present invention comprises use of compositions made from acombination of more than one material to form the occlusion,particularly compositions that comprise materials that cure orpolymerize by differing mechanisms. For example, the compositions maycomprise a combination of two materials, one of which cures orpolymerizes because an activating agent is present and the other cures,polymerizes or solidifies, all of which are interchangeable terms,because of the pH of the environment in which it is placed. Componentsof the mixture may serve different or overlapping roles; for example, atissue adhesive component may primarily serve to minimize expulsion ofthe implant while tissue in-growth is occurring, while another componentmay primarily initiate or support the tissue growth. The tissue adhesivecomponent may be selected from the group of materials containing thecyanoacrylates, polyacrylic acids, polyethylene glycols, modifiedpolyethylene glycols, thrombin, collagen, collagen-based adhesives,fibrin, fibrin glue compositions,gelatin-resorcinol-formaldehyde-glutaraldehye (GRFG) glue, autologousblood in combination with collagen and/or thrombin, crosslinked albuminadhesives, modified glycosaminoglycans,poly(N-isopropylacrylamide)-based adhesives, alginates, chitosan, andgelatin, crosslinked with carbodiimide or genepin, among others, in aproportion of the overall composition from about 5% to 50%, from about5% to 25%, from about 10% to 50%, or from about 10% to 25%. The materialadded primarily for the initiation or support of tissue ingrowth may bechosen from the group consisting of solid or solvated resorbablepolymers, including the resorbable polyesters or their copolymers. Thetissue ingrowth component, including or excluding the presence ofsolvent, may comprise from about 20% to 80%, from about 50% to 80%, fromabout 40 to 70%, or from about 50% to 90% of the overall composition.When a copolymer is used the percentage of each polymer within thecopolymer will be from about 25% to 75%.

Additional components may be included to stabilize the overall mixtureor to control the viscosity, curing time, resorption timeframe,plasticity, or to enhance visualization of the material. Such agents mayinclude: polymerization inhibitors and stabilizers including, forexample sulfonic acid, lactic acid, acetic acid, sulfur dioxide,lactone, boron trifluoride, hydroquinone, hydroquinone monomethyl ether,catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol, t-butyl catechol, organic acid, butylated hydroxyl anisole,butylated hydroxyl toluene, t-butyl hydroquinone, alkyl sulfate, alkylsulfite, 3-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan, andalkyl sulfide; emulsifying agents such as polyvinyl alcohol; echogenicagents such as microbubbles of air or gas, microparticles or spheres ofcrosslinked albumin with entrapped air or gas (Albunex), sonicatedalbumin, gelatin-encapsulated air or gas bubbles, nanoparticles,microparticles, spheres, or microcapsules of resorbable polyesters orother resorbable materials with entrapped air or gas, particles of othermaterials with entrapped air or gas; contrast agents such as goldparticles; viscosity-modifying materials such as crosslinkedcyanoacrylate, polylactic acid, polyglycolic acid, lactic-glycolic acidcopolymers, polycaprolactone, lactic acid-caprolactone copolymers,poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates,copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates,and copolymers of alkyl methacrylates and butadiene; and plasticizerssuch as dioctyl phthalate, dimethyl sebacate, trethyl phosphate,tri(2-ethylhexy)phosphate, tri(p-cresyl)phosphate, glyceryl triacetate,glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropylmyristate, butyl stearate, lauric acid, dibutyl phthalate, trioctyltrimellitate, and dioctyl glutarate. The composition may further containcolorants such as dyes and pigments. The total amount of these agentsmay comprise from about 0.1% to 10%, from 1% to 10%, or from 5% to 20%of the overall composition.

The combination of two or more materials that cure by differentmechanisms, including contact with tissue or the appropriate curingenvironment for example, conditions such as aqueous, ionic, temperature,or pH, chemical crosslinking, or solvent dissipation, among others, iscontemplated by the current invention. The combination of one or morematerials that cure by one or more mechanisms combined with one ormaterials that are pre-cured or pre-formed into particles, spheres, orother structures, is also contemplated by the current invention.

The present invention contemplates the use of pre-formed solid materialssuch as particles, spheres, capsules, or the like, in combination with aliquid or semi-solid material. The pre-formed solids may comprisedegradable or resorbable materials and may have enhanced ultrasoundvisibility or may serve to enhance ultrasound visibility of thecomposite occlusive material. The particles as contemplated may benanoparticles of an average size ranging from about 100 to 2000nanometers, about 100 to 1000 nanometers, about 250 to 2000 nanometers,or about 500 to 2000 nanometers in diameter. Particles may also bemicroparticles with an average size ranging from about 0.1 to 1000micrometers, about 0.1 to 250 micrometers, about 1 to 500 micrometers,about 50-500 micrometers, about 100-750 micrometers, or about 250 to1000 micrometers. The liquid or semisolid material acts as a transportmedium for the pre-formed solids and then cures in situ, entrapping thesolids. The particles may be coated with or contained within a materialthat enhances their miscibility with the liquid or semi-solid materialor minimizes the tendency of the particles to promote the prematurecuring of the liquid or semi-solid material prior to delivery. Coatingmaterials may include extremely low moisture content formulations of theparticulate constituent materials or other polymers or copolymerscontaining, for example, caprolactone, poly-.beta.-hydroxybutyrate,delta-valerolactone, as well as polyvinylpyrrolidone, polyamides,gelatin, albumin, proteins, collagen, poly(orthoesters),poly(anhydrides), poly(.alpha.-cyanoacrylates), poly(dihydropyrans),poly(acetals), poly(phosphazenes), poly(urethanes), poly(dioxinones),cellulose, and starches. The following patents and U.S. patentapplications teach manufacturing methods for creating echogenicparticles for use in ultrasound contrast agents: U.S. Pat. Nos.5,352,436; 5,562,099; 5,487,390; 5,955,143; 2004/0161384; 2004/0258761;and 2004/0258769. Particles made by these methods are contemplated bythe present invention.

The present invention also comprises methods for sequential applicationsof the same or different materials. For example, a composition of theoccluding material that functions as the in situ curable material may beplaced in the site or sites, and an adhesive composition may be appliedseparately either before or after the curable material so as to fix theimplanted material in place, thus lowering the risk of expulsion. The insitu curable materials may cure or solidify in the native environment ofthe fallopian tube, or the curing may require the presence of an energysource, such as light, heat, other electromagnetic waves, sound waves,or microwaves or the presence of an initiator and/or accelerator forcuring. The additional energy sources may be provided by the deliverydevice or another introductory vehicle or by sources outside the body.

The end structure of a delivery device may have alternative shapes thataid in maintaining the end at the site, aid in delivery of occlusivematerial, aid in removal of the delivery device from the site, aid inlocalizing the occlusion and other shapes and designs for functions bythe end. For example, a delivery device used for occluding the fallopiantubes in a mammal, having an end that is placed within the uterinecornua at or near the tubal ostia, may have end structures that comprisea shape that aids in delivery of the occlusive material, for example bymaintaining it in position. This end structure may function to guide tipplacement of the delivery system or anchor the arm ending to and/orcover the ostium of the tube and may take the form of a nozzle, cup, orballoon. A nozzle, cup or balloon is useful for preventing leakage ofcompositions of in situ curable material away from the implantationsite. Preferably, the end structures do not adhere to the implantablematerial although the use of an absorbable, detachable end structurethat may adhere to the implantable material and be left in place afterremoval of the remainder of the delivery system is also contemplated.Using a device having a structure that conforms to the shape of theuterine cornua, maintaining localized delivery to at least one ostiaeliminates the need to cannulate into the fallopian tube.

The present invention comprises methods for female sterilization whereinthe delivery device is not inserted into the fallopian tube and in whichthe occlusive material is introduced within the uterine cornua at ornear the tubal ostia affecting portions of the endometrium and/or tubalepithelium. The extent of the occlusion, such as the portion of theuterine cornua and fallopian tube blocked by the occlusive material, maybe controlled by modification of the curing time, viscosity, and amountof material delivered. The current invention comprises methods foreffective blockage of a conduit, such as a fallopian tube, by occludinga minimal portion of the fallopian tube. Such occlusion may block aconduit for less than 1.0 mm of the length of the conduit, for less than1 cm of the length of the conduit, for less than 3 cm of the length ofthe conduit, or for less than 5 cm of the length of the conduit. Forexample, in occluding a fallopian tube, an embodiment of the presentinvention comprises methods of application of an occluding material suchthat no more than 5 cm of the fallopian tube is occluded. In affectingthis length of tube, the anatomical areas of the fallopian tube targetedfor occlusion include the areas within the uterine wall (theinterstitial segment) and early portions of the isthmic section. Thepresent invention may not be dependent on the length, width or depth ofthe solidified occluding material, and the extent of the solidifiedoccluding material may be dependent on whether subsequent reversal ofthe occlusion is desired. If reversal of the occlusion is contemplatedat the time of occluding, a minimal amount of occlusion may be achieved,thus allowing for more ease in reversing the occlusion and opening theconduit.

In one method of delivery of the occlusive material, pressure generatedin the lumen of the delivery system forces the occlusive materialthrough the delivery device, including at least one opening in at leastone delivery end, out of the device and into the area to be blocked.Once the occlusive material has been delivered, the delivery device isremoved in whole or in part from the patient (the end structure may bedetachable and fashioned from a resorbable material designed to be leftin place). For example, once the occlusive material is delivered to thesite or the occlusive material cures in situ, the delivery device can becollapsed, re-folded, re-sheathed, or directly removed in one or morepieces from the patient.

The compositions of the present invention comprise occlusive materialsand may further comprise one or more agents that are capable ofproviding other functions, including but not limited to, a curablecarrier for the occlusive material, allowing for controlled release of asubstance, enhancing the ability of the occlusive material to causefibrosis or inhibit contraception. Quinacrine is well established tocreate scarring of the tubal epithelium and cause tubal blockage. Incombination with the occlusive material, low dosages of quinacrine orother sclerotic agents, such as tetracycline, may assist in creation ofthe fibrous tissue blockage. The compositions of the present inventioncomprise fibrous tissue growth promoting agents such as growth factorsor pro-inflammatory reagents that are known to those skilled in the art.U.S. Pat. No. 3,803,308 teaches that the instillation of copper or zincsalts alone into the uterus inhibits contraception. Current copperintrauterine devices have incorporated this concept. The presentinvention comprises compositions comprising copper salts or othermetallic elements in addition to the occlusive material. Inclusion ofhormonal contraceptives within the occlusive material to limit furtherthe risk of pregnancy during the timeframe of tissue ingrowth iscontemplated.

The present invention comprises methods for using energy-deliveringdevices to initiate or completely form an occlusion. Such methodscomprise activities at the site of the placement of the occlusivematerials to aid in the formation of tissue growth and/or biodegradationof the occlusive material. Such activities include, but are not limitedto, use of cautery methods, bipolar coagulating current, a highfrequency generator to produce a tissue damaging current, and use oflaser, light, microwave, and radiofrequency energy. Devices forproviding such activities and uses thereof are taught in U.S. Pat. Nos.4,700,701; 5,095,917; 5,474,089; 5,954,715; and 6,485,486.

The present invention also comprises delivery systems, methods anddevices for removing at least one occlusion at the occluded site. Asused herein, the term reversing the occluded site, means making theconduit capable of transporting again. Making the conduit capable oftransporting can include, but is not limited to, removal of the originaloccluding material, creating a new lumen through the occluded site, suchas forming a channel through the occluding material or the in-growntissue at the occluded site, or by-passing the occluded site. Themethods of the present invention comprise delivery of devices that placepermanent plugs within one or more conduits, simultaneously orsequentially, wherein such plugs are structured such that a device ofthe present invention can be used to remove the plugs at a later time.Structures for such plugs are taught U.S. Pat. No. Re. 29,345. Suchplugs are not resorbable or biodegradable by bodily actions and thusincorporate means for anchoring the plugs within the conduit. Theocclusion may be removed from the conduit by destruction of theoccluding material. For example, shockwaves can be used to shatter thematerial, similar to that used in lithotripsy methods, and the materialis expelled from the conduit. Chemical or biological means, such asinstillation of solvents or enzymes, can be used to disintegrate theocclusion. Removal devices of the present invention can be used toaffect one or both fallopian tubes that have occluding material therein,by physical removal of plugs, provision of materials that recanalize theoccluding site, or that mechanically form a new channel through oraround the occluded site. The device may also deliver a stent or otherdevice to ensure that the new channel remains open. U.S. Pat. Nos.4,983,177; 5,989,580; 4,664,112 and others teach methods forreversibility of occluded sites. In methods for reversing the blockageof fallopian tubes, the present invention contemplates systems, methodsand devices that are capable of reversing the occlusion in eachfallopian tube under non-invasive visualization and without removal andreinsertion or the need to reposition substantially the delivery deviceuntil both tubes are unblocked. Although it may be desirable to open thetubes one at a time, the ability to reach both tubes under non-invasivevisualization and without the withdrawal and reintroduction ofinstrumentation represents an advantage over the prior art.

In one aspect of the present invention in which a partially or fullyresorbable material is used to cause occlusion of a conduit, minimal orno permanent foreign body remains in position. In fallopian tubeocclusion, the occlusion is located at or near the ostium of the tube,making non-surgical access simple. A catheter with a working head forthe removal of an occlusion in a vessel or other body passageway can beused with the delivery device. A method for reversal of such blockedtubes incorporates the use of a catheter-based delivery system similarto that used for the introduction of the occlusive material. In thisaspect of the invention, the channel or channels of the delivery deviceare used for the introduction of a stiff or cutting catheter or acatheter for instillation of a dissolution medium (e.g., enzyme orsolvent) that recanalizes the blocked section(s) of the tube. A stent orother device to maintain the opening may be placed through the deliverydevice as well.

In general, the present invention comprises methods for occluding atleast one conduit in a human or animal body, comprising, providing adelivery system capable of delivering an effective amount of acomposition comprising an occlusive material, wherein the deliverysystem comprises a delivery device comprising at least an introducershaft for providing at least two catheters; two catheters, eachcomprising an end structure on a delivery end and attachment means on aproximal end, a composition comprising an occlusive material, and meansfor providing the composition comprising an occlusive material into andthrough the catheters; delivering an effective amount of the compositioncomprising an occlusive material at or near the target site such thatthe material occludes the lumen of the conduit; and occluding theconduit with the composition comprising an occlusive material within thelumen of the conduit. Means for providing the delivery compositioninclude, but are not limited to, syringes and pressure systems, pumps,containers with plungers to force material into the catheters, or othermethods and devices for moving flowable material through a catheter ortube. The methods further comprise opening conduits, whether the conduitis occluded by methods of the present invention or by other methods orprocesses, including natural and synthetic or medical processes. Themethods may comprise occluding two conduits without removal andre-introduction or substantial repositioning of the introducer shaft.Such a method may be used to treat fallopian tubes of a mammal, andprovides methods of contraception.

The compositions used in the methods of the present invention comprisingthe occlusive material may be mixed prior to delivery to the lumen. Thecompositions may comprise a liquid tissue adhesive and a solvatedpolymer, wherein the composition cures in situ. The compositioncomprising the occlusive material may be ultrasound visible. Theultrasound visible material may comprise microbubbles of air or gas ormicroparticles of a material that entrap air or gas. Compositions of thepresent invention comprise compositions wherein the liquid tissueadhesive is cyanoacrylate, polyacrylic acids, polyethylene glycols,modified polyethylene glycols, thrombin, collagen, collagen-basedadhesives, fibrin, fibrin glue compositions,gelatin-resorcinol-formaldehyde-glutaraldehye (GRFG) glue, autologousblood in combination with collagen or thrombin, crosslinked albuminadhesives, modified glycosaminiglycans,poly(N-isopropylacrylamide)-based adhesives, alginates, or chitosan orgelatin, crosslinked with carbodiimide or genepin; and the solvatedpolymer is a resorbable polyester, including polylactide, polyglycolide,or polycaprolactone or copolymers of these materials, includingpoly(lactide-/glycolide) acid (PLGA) orpoly(lactide-co-.epsilon.-caprolactone) (PLCL). The compositions may bevisible by ultrasound. The compositions may further comprise tissuescarring agents, fibrosis agents, fertilization inhibitors,contraceptive agents, tissue growth promoters, hormones, polymerizationinhibitors, polymerization stabilizers, emulsifying agents, echogenicagents, contrast agents, viscosity-modifying materials, plasticizers,colorants or combinations thereof.

The cured compositions of the present invention swell less than 20%, andmay be about 20% to about 100% substantially resorbed in a range ofabout 30 to about 365 days. Once resorbed the occlusion may bemaintained by tissue ingrowth.

Compositions of the present invention may also comprise a liquid tissueadhesive and particles. The particles may be nano- or micro-particlescomprising spheres of resorbable polymers. The particles may be fromabout 0.1 micrometer to about 1000 micrometers in diameter. Thecompositions may be viewable by ultrasound. The compositions may furthercomprise a curable carrier for the occlusive materials, a controlrelease agent, tissue scarring agents, fibrosis agents, fertilizationinhibitors, contraceptive agents, tissue growth promoters, hormones,polymerization inhibitors, polymerization stabilizers, emulsifyingagents, echogenic agents, contrast agents, viscosity-modifyingmaterials, plasticizers, colorants or combinations thereof.

The present invention comprises methods for contraception comprisingproviding a delivery system capable of delivering an effective amount ofa composition comprising an occlusive material, wherein the deliverysystem comprises a delivery device comprising at least an introducershaft for providing at least two catheters; two dual lumen ballooncatheters; a composition comprising an occlusive material and means forproviding the composition comprising an occlusive material into andthrough the catheters; delivering an effective amount of the compositioncomprising an occlusive material at or near the target location suchthat the material occludes the lumen of at least one fallopian tube; andoccluding the fallopian tube with the composition comprising anocclusive material within the lumen of the conduit.

The present invention comprises devices, including contraceptivedevices, comprising an introducer shaft for providing at least twocatheters; two catheters, each comprising an end structure at thedelivery end; a composition comprising an occlusive material, and meansfor providing the composition comprising an occlusive material into andthrough the catheters. The end structure may be a cup, nozzle, or aballoon. The devices may further comprise a delivery device stabilizerfor holding the contraceptive device in place once positioned. Thedelivery device stabilizer may fit over or attach to the cervix or fitinto or expand within the cervix to hold the device in position.

The present invention also comprises systems and methods for openingoccluded conduits. A method comprises providing a delivery devicecomprising at least an introducer shaft for providing at least twocatheters; two catheters, each comprising an end structure at thedelivery end; and means for re-opening the conduit; and re-opening oropening the conduit. A device that may be used to open conduitscomprises at least an introducer shaft for providing at least twocatheters; at least one catheter, comprising a stationary device at oneend; means for holding the delivery system in place upon positioning;and means for opening the conduit. Means for opening the conduitcomprise device or members for providing shockwaves to shatter theoccluding material, chemical means including solvents, biological meansincluding enzymes, or mechanical means including stiff or cuttingcatheter ends to recanalize the lumen. The method may further comprisemaintaining the opening of the conduit by providing a stent within thelumen of the conduit.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a”, “an”, and “the” include plural referentsunless the context clearly dictates otherwise.

All patents, patent applications and references included herein arespecifically incorporated by reference in their entireties.

It should be understood, of course, that the foregoing relates only toexemplary embodiments of the present invention and that numerousmodifications or alterations may be made therein without departing fromthe spirit and the scope of the invention as set forth in thisdisclosure.

Although the exemplary embodiments of the present invention describe indetail methods, delivery systems, and compositions to occlude thefallopian tubes of human, the present invention is not limited to theseembodiments. There are numerous modifications or alterations that maysuggest themselves to those skilled in the art for use of the methods,delivery systems, and compositions herein for the occlusion of a varietyof conduits in both human and non-human mammals.

The present invention is further illustrated by way of the examplescontained herein, which are provided for clarity of understanding. Theexemplary embodiments should not to be construed in any way as imposinglimitations upon the scope thereof. On the contrary, it is to be clearlyunderstood that resort may be had to various other embodiments,modifications, and equivalents thereof which, after reading thedescription herein, may suggest themselves to those skilled in the artwithout departing from the spirit of the present invention and/or thescope of the appended claims.

EXAMPLES Example 1 Preparation of Implantable Material A

A solution of 25/75 poly lactide-co-.epsilon.-caprolactone (PLCL) wasprepared 50% by weight in n-methyl-pyrrolidone (NMP) and sterilized. Amixture of 2-methoxypropyl cyanoacrylate (MPCA) with a biocompatibleacid, in this case glacial acetic acid (AA), was prepared containingapproximately 1 part MPCA and 1 part AA and sterilized. Implantablematerial A was prepared immediately prior to use by mixing 0.8 cc PLCLsolution with 0.2 cc MPCA mixture until homogeneity of the mixture wasachieved. The resultant mixture initially warms indicative of curing butremains adhesive to tissue and flowable through a 20G IV catheter for atleast 15 min at room temperature in the absence of an aqueousenvironment. In contact with either water or animal tissue, theimplantable material completes its curing quickly, forming a semi-solidmaterial that is compressible and flakes relatively easily.

Example 2 Preparation of Implantable Material B

A solution of 50/50 poly lactide-co-glycolide (PLGA) was prepared 25% byweight in ethyl alcohol (EtOH) and sterilized. A mixture of butylcyanoacrylate (BCA) with AA was prepared containing approximately 2parts BCA and 1 part AA and sterilized. Implantable material B wasprepared immediately prior to use by mixing 0.4 cc PLGA solution with0.4 cc BCA mixture until homogeneity of the mixture was achieved. Theresultant mixture initially warms indicative of curing but remainsstrongly adhesive to tissue and flowable through a 20G IV catheter forat least 15 min at room temperature in the absence of an aqueousenvironment. In contact with either water or animal tissue, theimplantable material completes its curing quickly, forming a relativelyincompressible semi-solid material that fractures on attempted bending.

Example 3 Preparation of Implantable Material C

Particles of 50/50 PLGA were prepared by dissolving PLGA in methylenechloride to create a 25% weight/volume solution, emulsifying in a 0.3%polyvinyl alcohol (PVA) solution, and further addition of PVA solutionwith 2% isopropyl alcohol to remove solvent. Particles were collected,lyophilized, and sterilized. Particles (0.25 g) were added to 0.75 g ofa sterilized mixture containing 2 parts BCA and one part AA. Theresulting particulate suspension was flowable at room temperature butcured on contact with water or animal tissue, forming a stiff, adherentmaterial.

Example 4 Preparation of Implantable Material D

Particles of 50/50 PLGA were prepared as described in Example 3 with theaddition of hydroquinone (0.5%) to the PVA emulsification, resulting inthe entrapment of hydroquinone on the surface of the particles. Theparticles were collected, lyophilized, and sterilized. Particles (0.25g) were added to 0.75 g of sterilized BCA. The particulate suspensionremained flowable at room temperature with no indication ofcyanoacrylate polymerization. The composition hardened on exposure towater or tissue, forming a stiff, adherent material.

Example 5 Study of 3 Implantable Materials in the Rabbit Fallopian Tube

Three candidate materials prepared similarly to the previous exampleshave been studied for their ability to create a mechanical occlusion andgenerate a tissue ingrowth response when placed into the fallopian tubesof rabbits. A fourth material, methyl cyanoacrylate (MCA), previouslyused to effect female sterilization in animals and humans but shown tohave an unacceptable biocompatibility profile, was used as a control.Each of the test and control materials was placed into the fallopiantubes of three New Zealand white rabbits through an open procedure inwhich a 20G IV catheter was used as the delivery system. Materials wereinfused through the catheter into the cornual aspect of the right andleft uterine body; finger pressure was used to prohibit backward flow ofthe material into the remainder of the uterus. Forward flow of thematerial was stopped once materials were seen within the cul-de-sac(i.e., peritoneal spill had occurred) or the full volume of material hadbeen delivered. It was noted that, in comparison to the control materialwhich cured very rapidly, sticking to the catheter, and with a high heatof curing, the test materials had a longer curing timeframe (within thetime prior to closure but sufficiently long to remove the catheterwithout adhesion) and did not generate as much heat. Once both right andleft tubes had been treated, the reproductive organs were repositionedwithin the pelvis, and the incision was closed. At 14 days, the animalswere sacrificed. Dye infusion testing demonstrated that the fallopiantubes of all animals were blocked. One test material had generated anexcessive amount of inflammation and adhesions and was ruled out. Theremaining test materials and the control generated an appropriate tissueresponse, completely blocking the lumen of the fallopian tube withinflammatory cells and debris.

Example 6 Use of the Delivery System in Explanted Human Uteri

A prototype delivery system comparable to that shown in FIG. 1 was usedto delivery dye and occlusive material to the fallopian tubes of threeexplanted human uteri obtained in accordance with the rules of theinstitution's Institutional Review Board. In each case, the explanteduterus was placed on an examination table in anatomic position, and theshaft of the introducer was placed transcervically until the tip reachedthe top of the uterine fundus as determined by tactile feel. Each of twoballoon catheters was then advanced through the channel in theintroducer until it was felt to lodge within the cornual aspect of theuterus. The balloons were inflated until resistance was felt. The uteruswas then bivalved to allow for visualization of the device, which, ineach case, was seen to be appropriately placed. One case represented anormal, multiparous uterus, while two cases demonstrated significantleiomyomatous pathology, indicating that the presence of fibroidsoutside the midline or the cornua does not interfere with the successfuluse of the delivery system. After successful placement was confirmed, aseries of liquid injections through the catheters was conducted: firstwith saline to confirm patency, second with a hematoxylin dye todemonstrate that backflow into the uterine cavity did not occur, andfinally with an occlusive material from the animal study in the previousexample to demonstrate full functionality of the system in humans. Ineach case tested, dye demonstrated forward flow without leakage into theuterine cavity, and the material was successfully delivered.

Example 7 Occluding Compositions

Component A Component B Additive(s) Functionality of Additive 50%Gelatin-resorcinol 50% Formaldehyde-glutaraldehyde — — 50%Gelatin-resorcinol 50% Formaldehyde-glutaraldehyde Microbubbles of airUltrasound visibility 50% Gelatin-resorcinol 50%Formaldehyde-glutaraldehyde Progesterone-estrogen - Inhibition ofovulation dissolved in component B during maturation of blockage 50%Gelatin-resorcinol 50% Formaldehyde-glutaraldehyde Tetracyline -dissolved in Promotion of scarring or component B fibrosis 50%Gelatin-resorcinol 50% Formaldehyde-glutaraldehyde bFGF, EGF - dissolvedin Induction of tissue component B ingrowth 50% Gelatin-resorcinol 50%Formaldehyde-glutaraldehyde Gold particles suspended X-ray visibility incomponent A 50% Gelatin-resorcinol 50% Formaldehyde-glutaraldehydeCopper sulfate - dissolved Inhibition of ovulation or suspended inand/or enhanced MRI component A visibility 70% Fibrin glue 30%poly-L-lactide dissolved 50% by — — weight in NMP 70% Fibrin glue 30%poly-L-lactide dissolved 50% by Microbubbles of air Ultrasound weight inNMP visibility 70% Fibrin glue 30% poly-L-lactide dissolved 50% byProgesterone-estrogen - Inhibition of ovulation weight in NMP dissolvedin component B during maturation of blockage 70% Fibrin glue 30%poly-L-lactide dissolved 50% by Tetracyline - dissolved in Promotion ofscarring or weight in NMP component B fibrosis 70% Fibrin glue 30%poly-L-lactide dissolved 50% by bFGF, EGF - dissolved in Induction oftissue weight in NMP component B ingrowth 70% Fibrin glue 30%poly-L-lactide dissolved 50% by Gold particles suspended X-rayvisibility weight in NMP in component A 70% Fibrin glue 30%poly-L-lactide dissolved 50% by Copper sulfate - dissolved Inhibition ofovulation weight in NMP or suspended in and/or enhanced MRI component Avisibility 11% n-butyl cyanoacrylate 89% poly-DL-lactide-co-glycolide —— dissolved 50% by weight in NMP 11% n-butyl cyanoacrylate 89%poly-DL-lactide- co-glycolide Microbubbles of air Ultrasound visibilitydissolved 50% by weight in NMP 10% n-butyl cyanoacrylate 80%poly-DL-lactide-co-glycolide 10% lactic acid, Inhibition of dissolved50% by weight in NMP Microbubbles of polymerization, Ultrasound airvisibility 11% n-butyl cyanoacrylate 89% poly-DL-lactide-co-glycolideProgesterone-estrogen - Inhibition of ovulation dissolved 50% by weightin NMP dissolved in component B during maturation of blockage 11%n-butyl cyanoacrylate 89% poly-DL-lactide-co-glycolide Tetracyline -dissolved in Promotion of scarring or dissolved 50% by weight in NMPcomponent B fibrosis 11% n-butyl cyanoacrylate 89%poly-DL-lactide-co-glycolide bFGF, EGF - dissolved in Induction oftissue dissolved 50% by weight in NMP component B ingrowth 11% n-butylcyanoacrylate 89% poly-DL-lactide-co-glycolide Gold particles suspendedX-ray visibility dissolved 50% by weight in NMP in component A 11%n-butyl cyanoacrylate 89% poly-DL-lactide-co-glycolide Copper sulfate -dissolved Inhibition of ovulation dissolved 50% by weight in NMP orsuspended in and/or enhanced MRI component A visibility 33%methoxypropyl 67% poly-DL-lactide-co-glycolide — — cyanoacrylatedissolved 50% by weight in NMP 33% methoxypropyl 67%poly-DL-lactide-co-glycolide Microbubbles of air Ultrasoundcyanoacrylate dissolved 50% by weight in NMP visibility 31%methoxypropyl 62% poly-DL-lactide-co-glycolide 7% lactic acid,Inhibition of cyanoacrylate dissolved 50% by weight in NMP Microbubblesof polymerization, air Ultrasound visibility 33% methoxypropyl 67%poly-DL-lactide-co-glycolide Progesterone-estrogen - Inhibition ofovulation cyanoacrylate dissolved 50% by weight in NMP dissolved incomponent B during maturation of blockage 33% methoxypropyl 67%poly-DL-lactide-co-glycolide Tetracyline - dissolved in Promotion ofscarring or cyanoacrylate dissolved 50% by weight in NMP component Bfibrosis 33% methoxypropyl 67% poly-DL-lactide-co-glycolide bFGF, EGF -dissolved in Induction of tissue cyanoacrylate dissolved 50% by weightin NMP component B ingrowth 33% methoxypropyl 67%poly-DL-lactide-co-glycolide Gold particles suspended X-ray visibilitycyanoacrylate dissolved 50% by weight in NMP in component A 33%methoxypropyl 67% poly-DL-lactide-co-glycolide Copper sulfate -dissolved Inhibition of ovulation cyanoacrylate dissolved 50% by weightin NMP or suspended in and/or enhanced MRI component A visibility 11%isohexyl 89% poly-DL-co-ε-co-caprolactone — — cyanoacrylate dissolved50% by weight in ethyl alcohol 11% isohexyl 89%poly-DL-co-ε-co-caprolactone Microbubbles of air Ultrasoundcyanoacrylate dissolved 50% by weight in ethyl alcohol visibility 10%isohexyl 80% poly-DL-co-ε-co-caprolactone 10% acetic acid, Inhibition ofcyanoacrylate dissolved 50% by weight in ethyl alcohol Microbubbles ofpolymerization, Ultrasound air visibility 11% isohexyl 89%poly-DL-co-ε-co-caprolactone Progesterone-estrogen - Inhibition ofovulation cyanoacrylate dissolved 50% by weight in ethyl alcoholdissolved in component B during maturation of blockage 11% isohexyl 89%poly-DL-co-ε-co-caprolactone Tetracyline - dissolved in Promotion ofscarring or cyanoacrylate dissolved 50% by weight in ethyl alcoholcomponent B fibrosis 11% isohexyl 89% poly-DL-co-ε-co-caprolactone bFGF,EGF - dissolved in Induction of tissue cyanoacrylate dissolved 50% byweight in ethyl alcohol component B ingrowth 11% isohexyl 89%poly-DL-co-ε-co-caprolactone Gold particles suspended X-ray visibilitycyanoacrylate dissolved 50% by weight in ethyl alcohol in component A11% isohexyl 89% poly-DL-co-ε-co-caprolactone Copper sulfate - dissolvedInhibition of ovulation cyanoacrylate dissolved 50% by weight in ethylalcohol or suspended in and/or enhanced MRI component A visibility 60%n-butyl 40% poly-DL-lactide-co-glycolide — — cyanoacrylatemicroparticles emulsified in 4% polyvinyl alcohol 60% n-butyl 40%poly-DL-lactide-co-glycolide Microbubbles of air Ultrasoundcyanoacrylate microparticles emulsified in 4% visibility polyvinylalcohol 60% n-butyl 30% poly-DL-lactide-co-glycolide 10% lactic acid,Inhibition of cyanoacrylate microparticles emulsified in 4% Microbubblesof polymerization, Ultrasound polyvinyl alcohol air visibility 60%n-butyl 40% poly-DL-lactide-co-glycolide 10% acetic acid, Inhibition ofcyanoacrylate microparticles emulsified in 4% Microbubbles ofpolymerization, Ultrasound polyvinyl alcohol air visibility 60% n-butyl40% poly-DL-lactide-co-glycolide Progesterone-estrogen - Inhibition ofovulation cyanoacrylate microparticles emulsified in 4% dissolved incomponent A during maturation of polyvinyl alcohol blockage 60% n-butyl40% poly-DL-lactide-co-glycolide Quinacrine - dissolved in Promotion ofscarring or cyanoacrylate microparticles emulsified in 4% component Afibrosis polyvinyl alcohol 60% n-butyl 40% poly-DL-lactide-co-glycolidebFGF, EGF - dissolved Induction of tissue cyanoacrylate microparticlesemulsified in 4% in component A ingrowth polyvinyl alcohol 60% n-butyl40% poly-DL-lactide-co-glycolide Gold particles X-ray visibilitycyanoacrylate microparticles emulsified in 4% suspended in polyvinylalcohol component A 60% n-butyl 40% poly-DL-lactide-co-glycolide Coppersulfate - Inhibition of cyanoacrylate microparticles emulsified in 4%dissolved or suspended ovulation and/or polyvinyl alcohol in component Aenhanced MRI visibility

REFERENCES

US PATENT DOCUMENTS 3,405,711 5,714,159 6,309,384 3,803,308 5,733,9506,346,102 3,858,586 5,736,152 6,357,443 Re 29,345 5,739,176 6,371,975 Re37,950 5,744,153 6,378,524 4,136,695 5,746,769 6,395,293 4,158,0505,747,058 6,401,719 4,160,446 5,759,563 6,413,536 4,185,618 5,780,0446,413,539 4,245,623 5,792,469 6,433,096 4,359,454 5,826,584 6,455,0644,509,504 5,866,554 6,458,147 4,606,336 5,888,533 6,461,631 4,664,1125,894,022 6,476,070 4,679,558 5,935,137 6,485,486 4,681,106 5,954,7156,514,534 4,700,701 5,962,006 6,514,535 4,700,705 5,968,542 6,526,9794,804,691 5,979,446 6,528,080 4,824,434 5,989,580 6,538,026 4,938,7635,990,194 6,565,557 4,983,177 6,010,714 6,579,469 5,065,751 6,019,7576,599,299 5,095,917 6,037,331 6,605,294 5,147,353 6,042,590 6,605,6675,278,201 6,066,139 6,607,631 5,278,202 6,068,626 6,620,846 5,324,5196,096,052 6,634,361 5,328,687 6,112,747 6,663,607 5,340,849 6,120,7896,676,971 5,350,798 6,130,200 6,679,266 5,469,867 6,143,352 6,682,5265,474,089 6,145,505 6,684,884 5,487,897 6,174,919 6,703,047 5,559,5526,176,240 6,723,144 5,612,052 6,179,832 6,723,781 5,632,727 6,297,3376,743,248 5,681,873 6,299,631 6,327,505 5,702,716 6,306,243 3,680,542

FOREIGN PATENT DOCUMENTS WO 81/00701 WO 98/31308 WO 94/24944 WO 99/07297WO 94/28803 WO 99/47073 WO 97/12569 WO 00/44323 WO 97/49345 WO 00/24374WO 97/42987 WO 01/37760 WO 98/26737 WO 02/39880 WO 03/070085

OTHER PUBLICATIONS

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What is claimed is:
 1. A method for delivering a fluid composition toone fallopian tube in a mammal, comprising, a) positioning at the cornuaof one fallopian tube of a mammal, an end structure of a catheter sothat a delivery end of the catheter is located within the uterine cornuaand is at or near a tubal ostium, wherein the end structure maintainsthe delivery end in the uterine cornua and aids in localized delivery ofthe fluid composition; b) delivering an effective amount of the fluidcomposition through and out the delivery end of the catheter so that atleast a portion of the fluid composition is delivered to the fallopiantube.
 2. The method of claim 1, wherein the end structure comprises anozzle, balloon, or a cup.
 3. The method of claim 1, further comprising,c) withdrawing the catheter.
 4. The method of claim 1, furthercomprising, imaging with sonography the uterus, the fallopian tube orboth, before the step a).
 5. The method of claim 3, further comprising,imaging with sonography the uterus, the fallopian tube or both, beforestep a) or after step c).
 6. The method of claim 3, further comprisingimaging with sonography the uterus, the fallopian tube or both, beforestep a) and after step c).
 7. A method for delivering a fluidcomposition to two fallopian tubes in a mammal, comprising, a)positioning at the cornua of a first fallopian tube of a mammal, an endstructure of a catheter so that the delivery end of the catheter islocated within the uterine cornua and is at or near a tubal ostium,wherein the end structure maintains the delivery end in the uterinecornua and aids in localized delivery of a fluid composition; b)delivering an effective amount of the fluid composition through and outthe delivery end of the catheter so that at least a portion of the fluidcomposition is delivered to the first fallopian tube; c) positioning atthe cornua of a second fallopian tube of a mammal, the end structure ofthe catheter of a) or an end structure of a second catheter so that thedelivery end of the catheter is located within the uterine cornua and isat or near a tubal ostium, wherein the end structure maintains thedelivery end in the uterine cornua and aids in localized delivery of afluid composition; and d) delivering an effective amount of the fluidcomposition through and out the delivery end of the catheter so that atleast a portion of the fluid composition is delivered to the secondfallopian tube.
 8. The method of claim 7, wherein the end structurecomprises a nozzle, balloon, or a cup.
 9. The method of claim 7, furthercomprising, e) withdrawing the catheter.
 10. The method of claim 7,further comprising, imaging with sonography the uterus, at least onefallopian tube, or both, before the step a).
 11. The method of claim 9,further comprising, imaging with sonography the uterus, at least onefallopian tube, or both, before step a) or after step e).
 12. The methodof claim 9, further comprising imaging with sonography the uterus, atleast one fallopian tube, or both, before step a) and after step e). 13.A method for delivering a fluid composition to two fallopian tubes in amammal, comprising, a) positioning at each cornua of two fallopian tubesof a mammal, the end structure of one catheter of a delivery systemcomprising two catheters, each catheter comprising an end structure, sothat a delivery end of the catheter is located within the uterine cornuaand is at or near a tubal ostium, wherein the end structure maintainsthe delivery end in the uterine cornua and aids in localized delivery ofa fluid composition; b) delivering an effective amount of the fluidcomposition through and out the delivery end of each catheter so that atleast a portion of the fluid composition is delivered to each of thefallopian tubes.
 14. The method of claim 13, wherein the end structurecomprises a nozzle, balloon, or a cup.
 15. The method of claim 13,further comprising, c) withdrawing the catheters from each fallopiantube.
 16. The method of claim 13, further comprising, imaging withsonography the uterus, the fallopian tube or both, before the step a).17. The method of claim 15, further comprising, imaging with sonographythe uterus, the fallopian tube or both, before step a) or after step c).18. The method of claim 15, further comprising imaging with sonographythe uterus, the fallopian tube or both, before step a) and after stepc).